Affinage

INSM1

Insulinoma-associated protein 1 · UniProt Q01101

Length
510 aa
Mass
52.9 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INSM1 is a nuclear C2H2 zinc-finger transcription factor that acts downstream of proneural factors (Ngn3, Ascl1/Mash1) to drive terminal differentiation of neuroendocrine, neuronal, and sensory lineages by repressing progenitor and alternative-fate gene programs (PMID:16951258, PMID:16511571, PMID:18094025, PMID:19542360, PMID:26453796). Its architecture combines an N-terminal regulatory/SNAG region with five C-terminal zinc fingers that bind a defined consensus DNA element and confer transcriptional repression (PMID:1634555, PMID:11842116). As a target of Ngn3/CBP and Ascl1, which bind and activate the INSM1 promoter/regulatory elements, INSM1 is induced at the progenitor-to-differentiated transition and can autoregulate its own promoter (PMID:11842116, PMID:16511571, PMID:17300785, PMID:19542360). Repression is executed through its SNAG domain, which recruits histone-modifying complexes including LSD1 (KDM1A), HDAC1/2, and the REST corepressors RCOR1-3, and through recruitment of cyclin D1 and HDAC-3 to target promoters such as insulin and NeuroD/beta2 (PMID:16569215, PMID:18417529, PMID:24227653, PMID:28667074, PMID:28049845). Beyond transcriptional repression, INSM1 binds cyclin D1 via its proline-rich N-terminus, disrupting cyclin D1–CDK4 association, causing pRb hypophosphorylation and cell-cycle arrest (PMID:19124461). In mature endocrine cells INSM1 partners combinatorially with Neurod1 and Foxa2 to maintain differentiated identity and insulin secretion (PMID:25828096). Loss of INSM1 produces failures or switches of cell fate across tissues—blocked endocrine, chromaffin, serotonergic/noradrenergic, and pulmonary neuroendocrine differentiation, transdifferentiation of outer to inner cochlear hair cells, retention of apical/proliferative progenitors, and autoimmune dysregulation in thymic epithelium (PMID:16951258, PMID:18094025, PMID:19542360, PMID:21284846, PMID:26453796, PMID:30305733, PMID:37990032). INSM1 is also embedded in oncogenic neuroendocrine circuits, supporting SCLC and neuroblastoma proliferation and modulating pancreatic neuroendocrine tumor phenotype (PMID:26456864, PMID:28667074, PMID:30796198).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1992 High

    Defining the protein's domain architecture established INSM1 as a candidate DNA-binding factor, framing all subsequent functional study.

    Evidence cDNA cloning and sequence/domain prediction identifying five C2H2 zinc fingers and an N-terminal putative prohormone region

    PMID:1634555

    Open questions at the time
    • No DNA target or transcriptional activity demonstrated
    • Functional role of the N-terminal domain unresolved
  2. 1994 High

    Showing the gene is intronless and maps to chromosome 20p completed its basic structural characterization.

    Evidence Genomic cloning, in vitro translation, and in situ hybridization

    PMID:8188699

    Open questions at the time
    • Does not address regulation or function
    • No cellular phenotype examined
  3. 2002 High

    Establishing INSM1 as a sequence-specific transcriptional repressor with a defined consensus site, autoregulation, and nuclear localization converted it from a sequence to a functional regulator and revealed an early interaction with CAP.

    Evidence GAL4 reporter and SELEX with GST-DBD, mutagenesis, plus yeast two-hybrid/Co-IP and GFP localization

    PMID:11842116 PMID:12079283

    Open questions at the time
    • Mechanism of repression (corepressors) not yet identified
    • Functional significance of the CAP interaction unclear
  4. 2003 High

    Identifying the NeuroD1/E47-bound E-box in the INSM1 promoter placed INSM1 within an endocrine transcription factor hierarchy as a transcriptional target.

    Evidence Promoter deletion reporters, EMSA, and mutagenesis

    PMID:12890672

    Open questions at the time
    • In vivo relevance of the E3 element not tested at this stage
  5. 2006 High

    Positioning INSM1 immediately downstream of Ngn3 and demonstrating it is essential for endocrine cell differentiation defined its core developmental role and its repressor mechanism via cyclin D1/HDAC recruitment.

    Evidence Ngn3-null epistasis and ChIP, Insm1 knockout mouse phenotyping, and ChIP/yeast two-hybrid/Co-IP for the cyclin D1–HDAC complex on NeuroD/beta2

    PMID:16511571 PMID:16569215 PMID:16951258

    Open questions at the time
    • Genome-wide target repertoire not defined
    • Direct versus indirect target distinction limited to candidate promoters
  6. 2007 High

    Demonstrating Ngn3/CBP occupancy and histone hyperacetylation at the INSM1 promoter clarified how the upstream proneural factor activates INSM1 transcription.

    Evidence ChIP for Ngn3 and CBP, adenoviral overexpression, and histone acetylation assays

    PMID:17300785

    Open questions at the time
    • Does not address downstream INSM1 targets
  7. 2007 High

    Extending INSM1 function to sympatho-adrenal differentiation placed it downstream of Mash1/Ascl1 and tied its loss to catecholamine-deficiency lethality.

    Evidence Insm1 knockout mouse with gene-expression and epistasis analysis

    PMID:18094025

    Open questions at the time
    • Direct INSM1 target genes in this lineage not identified
  8. 2008 High

    Mapping INSM1 expression to late/basal neuronal progenitors and establishing direct repression of the insulin promoter via cyclin D1/HDAC-3 refined both where and how INSM1 acts.

    Evidence ISH/IHC localization across neurogenic zones; reporter mutagenesis, ChIP in multiple systems, and morpholino knockdown for insulin repression; plus Shh-induced expression in cerebellar progenitors

    PMID:18205207 PMID:18231642 PMID:18417529

    Open questions at the time
    • Localization study single-lab and partly inferential
    • Shh-to-INSM1 link correlative for cerebellar progenitors
  9. 2009 High

    Biochemical reconstitution showed INSM1 binds cyclin D1 through its proline-rich N-terminus to disrupt cyclin D1–CDK4 and arrest the cell cycle, while genetics linked it to serotonergic/noradrenergic neuron differentiation downstream of Ascl1.

    Evidence Competitive pulldown, mutagenesis, Tet-on expression, xenografts; and Insm1-null mice with Ascl1 ChIP at the Insm1 regulatory element

    PMID:19124461 PMID:19542360

    Open questions at the time
    • How cell-cycle and transcriptional-repressor functions are coordinated unresolved
    • Direct serotonergic target promoters not all defined
  10. 2011 High

    Showing INSM1 drives the apical-to-basal, proliferative-to-neuronogenic transition of olfactory progenitors connected its expression pattern to a concrete progenitor-transition function.

    Evidence Insm1 knockout mouse with marker analysis and nucleoside pulse-chase

    PMID:21284846

    Open questions at the time
    • Molecular targets governing the transition not yet identified
  11. 2013 High

    Identifying the SNAG domain as the in vivo functional module that recruits LSD1/HDAC/CoREST machinery provided the mechanistic basis of INSM1-mediated repression.

    Evidence SNAG-deletion mouse, mass spectrometry of co-purifying proteins, and Co-IP

    PMID:24227653

    Open questions at the time
    • Stoichiometry and locus-specific composition of the complex not resolved
  12. 2014 High

    Transcriptomics of sorted endocrine progenitors and a non-canonical RACK1/insulin-receptor signaling role broadened INSM1's mechanistic repertoire beyond classical repression.

    Evidence Insm1(GFPCre) reporter, FACS and transcriptome analysis of pancreatic populations; and Co-IP/competitive binding with RACK1/InR plus phospho-AKT and ChIP

    PMID:24407176 PMID:25053427

    Open questions at the time
    • RACK1/InR signaling role is single-lab Medium-confidence
    • Cytoplasmic versus nuclear partition of these functions unclear
  13. 2015 High

    Defining a combinatorial Insm1/Neurod1/Foxa2 complex in mature beta cells and direct Hes1 repression in pulmonary neuroendocrine cells showed INSM1 maintains differentiated identity and antagonizes Notch effectors.

    Evidence Conditional beta-cell ablation with ChIP-seq/Co-IP and insulin-secretion assays; Ascl1-mutant epistasis with Insm1 ChIP at Hes1; plus N-myc positive-feedback work in neuroblastoma

    PMID:25828096 PMID:26453796 PMID:26456864

    Open questions at the time
    • Genome-wide cooperativity rules between the three factors not fully defined
    • N-myc feedback loop Medium-confidence single-lab
  14. 2017 High

    Demonstrating direct SNAG-mediated LSD1 binding required for SCLC gene expression, and INSM1–RCOR1/2 complexes phenocopying Rcor1/2 knockouts in brain, solidified INSM1 as a recruiter of REST-corepressor/LSD1 machinery with therapeutic relevance.

    Evidence Co-IP, LSD1-inhibitor disruption and siRNA phenocopy in SCLC; Co-IP plus double-knockout genetics, transcriptomics, and REST rescue in embryonic brain

    PMID:28049845 PMID:28667074

    Open questions at the time
    • Locus selectivity of LSD1/RCOR recruitment not resolved
    • How INSM1 represses REST itself unclear
  15. 2018 High

    Three studies showed INSM1 enforces cell-fate decisions: repressing IHC genes in outer hair cells, repressing Plekha7 to drive neural progenitor delamination, and feeding into the Shh/N-myc/Ascl1 circuit in SCLC.

    Evidence Cochlear conditional KO with transcriptomics/electrophysiology; in utero electroporation with Plekha7 CRISPR KO and rescue; promoter/ChIP and knockdown in SCLC

    PMID:29501727 PMID:29503187 PMID:30305733

    Open questions at the time
    • Direct INSM1 binding at all relevant fate-gene loci not exhaustively mapped
    • SCLC Shh circuit Medium-confidence single-lab
  16. 2019 Medium

    Linking INSM1 level to pancreatic neuroendocrine tumor phenotype connected its differentiation function to tumor aggressiveness and metastasis.

    Evidence RIP1-Tag2 mouse crosses, Insm1-KO cell lines, invasion/metastasis assays, and promoter methylation analysis

    PMID:30796198

    Open questions at the time
    • Single-lab; mechanism connecting INSM1 loss to stemness/invasion not defined
    • Causality of promoter hypermethylation not established
  17. 2021 Medium

    Showing MEN1/p53/Notch crosstalk controls INSM1 expression and nuclear localization extended understanding of how INSM1 is regulated in tumor contexts.

    Evidence PanNET mouse/cell/tissue models with Notch inhibition and MEN1/p53 manipulation, INSM1 immunostaining

    PMID:34352404

    Open questions at the time
    • Single-lab correlative regulation
    • Direct molecular link from MEN1/p53/Notch to INSM1 promoter not defined
  18. 2023 High

    Defining the Insm1→Ikzf2 cascade in cochlear hair cells and INSM1/Aire co-occupancy at superenhancers in thymic epithelium revealed lineage-specific downstream targets and a new immunological role.

    Evidence Cochlear gain/loss/double-KO/rescue genetics; and Insm1-mutant mice with mTEC transcriptomics, Insm1 ChIP, and autoimmune phenotyping

    PMID:37171961 PMID:37990032

    Open questions at the time
    • Whether Insm1 regulates Ikzf2 directly remains unresolved (indirect regulator)
    • Mechanism of INSM1–Aire co-regulation at superenhancers not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How INSM1 selects specific target loci across diverse lineages, and how its transcriptional-repressor and cyclin D1/cell-cycle functions are integrated, remains unresolved.
  • No unified model of context-specific target selection
  • Structural basis of zinc-finger DNA recognition in vivo not determined
  • Integration of nuclear repressor and cytoplasmic signaling roles unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 1
Partners
CCND1FOXA2HDAC1HDAC3KDM1ANEUROD1RACK1RCOR1
Complex memberships
INSM1-Neurod1-Foxa2 complexINSM1-cyclin D1-HDAC repressor complexLSD1/CoREST (KDM1A-RCOR-HDAC) complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 IA-1/INSM1 encodes a 510 amino acid protein with five C2H2 zinc-finger DNA-binding motifs in the C-terminal domain (aa 251-510) and a putative prohormone domain with dibasic conversion sites in the N-terminal domain (aa 1-250), establishing its basic domain architecture. cDNA cloning, sequence analysis, structural domain prediction The Journal of biological chemistry High 1634555
1994 The IA-1/INSM1 gene is intronless; both cDNA and genomic DNA yielded identical ~61 kDa protein products in in vitro translation, and the gene was chromosomally localized to the short arm of human chromosome 20. Genomic cloning, restriction mapping, sequencing, in vitro translation, in situ hybridization The Journal of biological chemistry High 8188699
2002 INSM1/IA-1 functions as a transcriptional repressor; the repressor activity resides predominantly in amino acids 168–263. Using SELEX with bacterially expressed GST-IA-1DBD, the consensus DNA-binding sequence was identified as TG/TC/TC/TT/AGGGGG/TCG/A, and zinc fingers 2 and 3 are sufficient for transcriptional activity. INSM1 can auto-regulate its own promoter and repress the NeuroD/beta2 promoter. GAL4-DBD fusion reporter assays, SELEX/random oligonucleotide binding, GST pulldown, co-transfection reporter assays, mutagenesis Nucleic acids research High 11842116
2002 INSM1 protein localizes exclusively to the nucleus when expressed in transfected cells. INSM1 interacts with Cbl-associated protein (CAP); this interaction was confirmed by yeast two-hybrid, in vitro pulldown, nuclear co-localization, and co-immunoprecipitation, with both proteins detected in the nucleus of insulinoma cells. GFP-INSM1 transfection/fluorescence microscopy, yeast two-hybrid screen, in vitro pulldown, co-immunoprecipitation Genomics High 12079283
2003 The NeuroD1/E47 heterodimer directly binds the proximal E-box (E3) element of the IA-1 promoter and activates IA-1 transcription; the E3 box (−426 to −65 bp region) is critical for tissue-specific promoter activity. Promoter deletion reporter constructs, EMSA, transient transfection, mutagenesis The Journal of biological chemistry High 12890672
2006 INSM1 functions as a transcriptional repressor of the NeuroD/beta2 gene by recruiting cyclin D1 and histone deacetylases (HDAC-1 and HDAC-3). Cyclin D1 was identified as an INSM1-interacting protein via yeast two-hybrid from a human fetal brain library; the interaction was confirmed by in vitro and in vivo pulldown. INSM1 forms a complex with cyclin D1 and HDAC-3 on the NeuroD/beta2 promoter, as confirmed by chromatin immunoprecipitation. Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter gene assays The Biochemical journal High 16569215
2006 Insm1 is essential for the development of pancreatic beta cells and intestinal endocrine cells. In Insm1 mutant mice, endocrine precursors form but fail to differentiate into hormone-positive cells; many genes encoding secretory machinery proteins are down-regulated. Insm1 thus controls a gene expression program comprising hormones and proteins of the secretory machinery. Insm1 knockout mouse, histology, immunohistochemistry, gene expression analysis Genes & development High 16951258
2006 IA1/INSM1 is a direct transcriptional target of Ngn3 in the embryonic pancreas. Ngn3 binds to chromatin at the IA1 promoter region and activates IA1 transcription. IA1 expression is absent in Ngn3-null embryos but is normal in embryos mutant for NeuroD1, Arx, Pax4, and Pax6 (factors downstream of Ngn3), placing IA1 immediately downstream of Ngn3 in the endocrinogenic transcription factor network. Chromatin immunoprecipitation, ectopic expression in adult pancreatic duct cells, mouse mutant analysis (epistasis) The EMBO journal High 16511571
2007 Neurogenin 3 (Ngn3) and its co-activator CBP occupy the INSM1 promoter, leading to hyper-acetylation of histone H3/H4 in the INSM1 promoter region; adenoviral Ngn3 induces endogenous INSM1 expression in pancreatic ductal cells through CBP recruitment. Chromatin immunoprecipitation (ChIP) for endogenous Ngn3 and CBP at INSM1 promoter, adenoviral overexpression, histone acetylation assay FEBS letters High 17300785
2007 Insm1 is an essential component of the transcriptional network controlling sympatho-adrenal lineage differentiation. In Insm1 mutant mice, differentiation of sympatho-adrenal precursors is delayed, accompanied by reduced proliferation; terminal differentiation of adrenal chromaffin cells is blocked. The transcription factors Mash1, Phox2a, Gata3, and Hand2 show deregulated expression in Insm1 mutants, indicating Insm1 acts downstream of Mash1 (Ascl1) in this network. Fetal lethality of Insm1 mutants is caused by catecholamine deficiency. Insm1 knockout mouse, gene expression analysis, epistasis/genetic interaction analysis Development (Cambridge, England) High 18094025
2008 INSM1 protein is expressed exclusively in the nuclei of late neuronal progenitors and nascent (but not mature) neurons throughout embryonic and adult neurogenesis; non-surface (basal/subventricular zone) progenitors express INSM1, whereas apically mitotic progenitors do not, paralleling the role of the C. elegans ortholog EGL-46 in terminal neurogenic divisions. In situ hybridization combined with immunohistochemistry in mouse and human embryos; cellular localization across multiple neurogenic regions The Journal of comparative neurology Medium 18205207
2008 INSM1 binds a specific site in the proximal insulin promoter and represses insulin gene transcription by approximately 50%. Repression is mediated by recruitment of cyclin D1 and HDAC-3 to the insulin promoter. ChIP in beta TC-1 cells, mouse fetal pancreas, and Ad-INSM1-transduced human islets confirmed endogenous INSM1 occupancy of the insulin promoter. Morpholino knockdown of INSM1 or cyclin D1 in fetal mouse pancreas enhances insulin promoter activity. Reporter gene assays with mutagenesis, ChIP, co-immunoprecipitation, morpholino knockdown The Journal of endocrinology High 18417529
2008 Insm1 is regulated downstream of Sonic Hedgehog signaling and is expressed in developing cerebellum granule cell progenitors; Insm1 and Nhlh1 are novel HH targets induced by Shh treatment in cultured cerebellar granule cell progenitors, and their expression is upregulated in HH-dependent medulloblastomas. Gene expression profiling, Shh treatment of cultured progenitors, Gli1 binding to Nhlh1 promoter Neoplasia (New York, N.Y.) Medium 18231642
2009 INSM1 binds directly to cyclin D1 via the cyclin box domain; the proline-rich N-terminal region of INSM1 is required for this binding. INSM1 binding to cyclin D1 disrupts cyclin D1–CDK4 association, induces hypophosphorylation of pRb, and causes cell cycle arrest. Mutation of proline residues abolishes cyclin D1 binding and abrogates cell cycle arrest. INSM1 overexpression inhibits proliferation of Panc-1 cells in vitro and in nude mouse tumor models. Competitive pulldown, co-immunoprecipitation, Tet-on inducible expression system, cell cycle synchronization, serum starvation, MTT assay, soft agar colony formation, nude mouse xenograft, mutagenesis The Journal of biological chemistry High 19124461
2009 Insm1 is essential for the differentiation of serotonergic and noradrenergic neurons in the hindbrain. A conserved cis-regulatory sequence of Insm1 is directly bound and activated by Ascl1 in the ventral hindbrain. In Insm1-null mice, serotonergic fate determinants Pet1, Lmx1b, and Gata2 are markedly downregulated; Tph2 (tryptophan hydroxylase 2, key serotonin biosynthesis enzyme) fails to be activated. Both Insm1 and Ascl1 coordinately specify Tph2 expression. In brainstem noradrenergic centers, tyrosine hydroxylase expression is delayed/deficient in Insm1 mutants. Insm1-null mouse genetics, Ascl1 chromatin occupancy (ChIP at Insm1 regulatory element), epistatic analysis of downstream transcription factors Development (Cambridge, England) High 19542360
2011 Insm1 promotes the transition of olfactory progenitors from apical/proliferative to basal/terminally-dividing and neuronogenic. Deletion of Insm1 in mice results in more apical progenitors expressing ASCL1, fewer basal/NEUROD1-expressing terminal progenitors, and fewer terminally dividing cells (confirmed by nucleoside analog pulse-chase). This role is partially conserved with the C. elegans ortholog egl-46. Insm1 knockout mouse, immunohistochemistry, nucleoside analog (BrdU/EdU) pulse-chase for cell division timing Neural development High 21284846
2013 Insm1 requires its N-terminal SNAG domain for function in vivo. The SNAG domain recruits histone-modifying factors including Kdm1a (LSD1), Hdac1/2, Rcor1-3, and other transcriptional regulators (Hmg20a/b, Gse1). Deletion of the SNAG domain in mice disrupted pituitary endocrine cell differentiation and caused upregulation of Notch pathway components and ectopic skeletal muscle gene expression, phenocopying full Insm1 deletion in the pituitary. SNAG domain deletion mouse model, mass spectrometry of Insm1 co-purifying proteins, co-immunoprecipitation, gene expression analysis Development (Cambridge, England) High 24227653
2014 INSM1 interacts with RACK1 through its proline-rich N-terminal region; this interaction disrupts RACK1–insulin receptor (InR) binding, enhancing InR-mediated signaling and increasing AKT phosphorylation. INSM1-enhanced AKT phosphorylation is blocked by the PI3K inhibitor LY294002. The INSM1/RACK1/InR pathway activates Nkx6.1 expression via increased acetyl-H4 modification of the Nkx6.1 promoter during AR42J cell trans-differentiation. Co-immunoprecipitation, competitive binding assay, phospho-AKT western blot, PI3K inhibitor treatment, ChIP for histone acetylation at Nkx6.1 promoter Cellular signalling Medium 24407176
2014 Insm1 promotes the transition from ductal progenitor to committed endocrine cell in the pancreas by repressing a progenitor cell program and activating genes for RNA splicing, cell migration, cell proliferation, and hormone secretion. Insm1 positively regulates Neurog3 (reducing a non-coding Neurog3 mRNA splice variant in its absence), and regulates the proliferation inhibitor Ripply3. Insm1(GFPCre) reporter allele, flow-cytometry cell sorting, transcriptome analysis of Insm1-null populations, genetic analysis of Ripply3 function Development (Cambridge, England) High 25053427
2015 Insm1 directly interacts with Neurod1 and Foxa2, and this trimeric complex binds regulatory sequences in the genome of mature pancreatic beta cells. Ablation of Insm1 in mature beta cells causes deficits in insulin secretion; adult mutant beta cells resemble immature neonatal beta cells in gene expression. Combinatorial Insm1/Neurod1/Foxa2 binding—not Insm1 binding alone—explains the majority of gene expression changes. Conditional Insm1 ablation in adult beta cells, Co-immunoprecipitation, ChIP-seq for all three factors, gene expression analysis, functional insulin secretion assay The EMBO journal High 25828096
2015 Insm1 is expressed downstream of Ascl1 in pulmonary neuroendocrine cells (Insm1 expression is absent in Ascl1-mutant lungs). Insm1 directly binds the Hes1 promoter and represses Hes1 expression; this Insm1-dependent Hes1 repression is required for neuroendocrine cell differentiation in the lung. Loss of Insm1 blocks terminal differentiation and upregulates Hes1 protein in neuroendocrine cells while interfering with Ascl1 maintenance. Ascl1 mutant mouse epistasis, Insm1 knockout mouse, ChIP for Insm1 on Hes1 promoter, immunohistochemistry, gene expression analysis Developmental biology High 26453796
2015 INSM1 increases N-myc stability in neuroblastoma by activating the PI3K/AKT/GSK3β pathway, suppressing N-myc phosphorylation at Thr-58 and thereby inhibiting N-myc degradation. N-myc in turn binds the E2-box of the INSM1 promoter and activates INSM1 expression, forming a positive-feedback loop. The Sonic hedgehog pathway induces this loop. Overexpression and knockdown in neuroblastoma cells, PI3K/AKT pathway inhibition, phospho-N-myc western blot, ChIP for N-myc at INSM1 promoter, invasion assay, xenograft nude mouse model Oncotarget Medium 26456864
2017 INSM1 interacts with LSD1 (KDM1A) via its SNAG domain, and this interaction is required for neuroendocrine-associated gene expression and SCLC cell proliferation. The irreversible LSD1 inhibitor T-3775440 disrupts the LSD1–INSM1 interaction, inhibiting expression of neuroendocrine genes such as ASCL1 and reducing SCLC proliferation. INSM1 silencing phenocopies T-3775440 effects on gene expression and proliferation. Co-immunoprecipitation (LSD1–INSM1), LSD1 inhibitor treatment, INSM1 siRNA knockdown, gene expression analysis, in vitro and in vivo proliferation assays Cancer research High 28667074
2017 INSM1 forms complexes with REST corepressors RCOR1 and RCOR2 in embryonic mouse brain progenitors. The Insm1-/- mouse phenocopies predominant brain phenotypes of the Rcor1/2 double knockout, including abnormally high neural progenitor numbers, fewer differentiated neurons/OPC, and defective interganglionic sulcus closure. A large number of genes are concordantly misregulated in both knockouts, and REST transcripts are upregulated in both; reducing REST to control levels in the Rcor1/2 KO partially rescues the interganglionic sulcus defect. Co-immunoprecipitation (INSM1–RCOR1/2 in embryonic brain), double-knockout mouse genetics, transcriptome analysis, REST rescue experiment Proceedings of the National Academy of Sciences of the United States of America High 28049845
2018 Insm1 is transiently expressed in nascent outer hair cells (OHCs) but not inner hair cells (IHCs). In the absence of INSM1, many OHCs trans-differentiate into IHCs: INSM1 represses a core set of IHC-enriched genes in embryonic OHCs, rendering them unresponsive to an IHC-inducing gradient. Upregulation of IHC-enriched genes in INSM1-deficient OHCs identifies candidate genes for IHC-specific differentiation. Insm1 conditional knockout mouse, transcriptome comparison of immature IHCs vs OHCs with/without INSM1, immunohistochemistry, electrophysiology Nature High 30305733
2018 Insm1 promotes delamination of neural progenitor cells (NPCs) from the ventricular surface during neocortex development by repressing Plekha7, an apical adherens junction belt-specific protein. Forced Insm1 expression converts apical to basal radial glia. CRISPR/Cas9 disruption of Plekha7 alone causes NPC delamination, and Plekha7 overexpression counteracts Insm1-induced delamination. In utero electroporation of Insm1, CRISPR/Cas9 knockout of Plekha7, Plekha7 overexpression rescue, live imaging, immunostaining Neuron High 29503187
2018 The Sonic hedgehog signaling pathway activates INSM1 expression in SCLC through N-myc and Ascl1, both of which bind the E2-box in the INSM1 promoter. INSM1 in turn crosstalks with the Shh-PI3K/AKT-N-myc/Ascl1-MEK/ERK1/2 transcriptional network, enhancing N-myc stability. Knockdown of INSM1 or Shh inhibitors reduce NE lung cancer cell growth. Promoter reporter assays, ChIP for N-myc and Ascl1 at INSM1 E2-box, INSM1 knockdown, Shh inhibitor treatment, western blot for N-myc stability Cellular signalling Medium 29501727
2019 Insm1 expression determines the phenotype of pancreatic neuroendocrine tumors in the RIP1-Tag2 mouse model: high Insm1 expression correlates with insulinoma (localized, hormone-secreting), while loss of Insm1 correlates with nonfunctioning metastatic PanNETs. In human cell lines, Insm1-deficient cells express stem cell markers, are more invasive in vitro, and metastasize at higher rates in vivo. INSM1 promoter is hypermethylated in human nonfunctioning PanNETs. Mouse genetic crosses (RIP1-Tag2), Insm1 KO cell lines, in vitro invasion assay, in vivo metastasis assay, promoter methylation analysis Oncogenesis Medium 30796198
2021 Cross-talk among MEN1, p53, and Notch signaling regulates INSM1 expression and subcellular localization in pancreatic neuroendocrine tumor cells. Loss of MEN1 in a p53 wild-type background results in increased nuclear INSM1 expression and cell proliferation. Inhibition of Notch signaling in a p53 wild-type background reduces PanNET cell proliferation by repressing INSM1 transcription and nuclear localization. PanNET mouse model, human cell lines, human tissue analysis, INSM1 localization by immunostaining, Notch inhibitor treatment, MEN1/p53 genetic manipulation Neoplasia (New York, N.Y.) Medium 34352404
2023 Epistasis analysis in cochlear hair cells reveals that Insm1 acts as a positive (but indirect) regulator of Ikzf2: Insm1 overexpression in IHCs leads to ectopic Ikzf2 expression; Ikzf2 expression is repressed in Insm1-deficient OHCs; forced Ikzf2 expression partially rescues OHC abnormalities in Insm1 mutants; and dual ablation of Insm1 and Ikzf2 produces the same OHC-to-IHC transdifferentiation phenotype as Insm1 ablation alone. This establishes a transcriptional cascade from Insm1 to Ikzf2 in OHC development. Insm1 overexpression in IHCs, Insm1 conditional KO, Ikzf2 conditional KO, Insm1/Ikzf2 double KO, Ikzf2 forced expression rescue, immunostaining Cell reports High 37171961
2023 Insm1 is broadly co-expressed with Aire in medullary thymic epithelial cells (mTECs). Insm1 mutation in mice downregulates Aire expression, dysregulates the mTEC gene expression program, alters mTEC subpopulations and tissue-restricted antigen expression, and causes autoimmune responses in peripheral tissues. Insm1 regulates gene expression in mTECs by direct chromatin binding; the majority of Insm1 binding sites are co-occupied by Aire and enriched in superenhancer regions. Insm1 mutant mouse, immunostaining, transcriptome analysis of mTECs, ChIP for Insm1 in mTECs, autoimmune phenotype assessment Cellular & molecular immunology High 37990032

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes & development 179 16951258
2015 INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms. American journal of clinical pathology 153 26386079
2006 IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas. The EMBO journal 149 16511571
2017 INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity. The American journal of surgical pathology 143 28719469
1992 A novel human insulinoma-associated cDNA, IA-1, encodes a protein with "zinc-finger" DNA-binding motifs. The Journal of biological chemistry 141 1634555
2017 Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer. Oncotarget 135 29088741
2018 INSM1 is a Sensitive and Specific Marker of Neuroendocrine Differentiation in Head and Neck Tumors. The American journal of surgical pathology 126 29438167
2009 Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 118 19246490
2018 Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 108 30154579
1992 Interleukin-6 down regulates the expression of transcripts encoding cytochrome P450 IA1, IA2 and IIIA3 in human hepatoma cells. Biochemical and biophysical research communications 101 1374245
2007 Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympatho-adrenal lineage. Development (Cambridge, England) 98 18094025
2018 Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 85 30305733
2017 Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor. Medical molecular morphology 82 28849340
2015 Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function. The EMBO journal 79 25828096
2017 LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B. Cancer research 78 28667074
2003 NeuroD1/E47 regulates the E-box element of a novel zinc finger transcription factor, IA-1, in developing nervous system. The Journal of biological chemistry 78 12890672
2002 Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence. Nucleic acids research 77 11842116
2016 A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases. Gynecologic oncology 73 27908529
2018 INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell Carcinoma. The American journal of surgical pathology 71 30080705
2018 Insm1 Induces Neural Progenitor Delamination in Developing Neocortex via Downregulation of the Adherens Junction Belt-Specific Protein Plekha7. Neuron 66 29503187
1993 IA-1, a new marker for neuroendocrine differentiation in human lung cancer cell lines. Cancer research 64 8364910
2018 INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 63 29327709
2017 REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation-differentiation balance in the developing brain. Proceedings of the National Academy of Sciences of the United States of America 63 28049845
2008 Transient expression of the conserved zinc finger gene INSM1 in progenitors and nascent neurons throughout embryonic and adult neurogenesis. The Journal of comparative neurology 60 18205207
2014 Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3. Development (Cambridge, England) 58 25053427
2020 INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas. American journal of clinical pathology 53 32128564
1991 The active sites of cytochromes P450 IA1, IIB1, IIB2, and IIE1. Topological analysis by in situ rearrangement of phenyl-iron complexes. The Journal of biological chemistry 52 1918043
2006 INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. The Biochemical journal 51 16569215
2020 Diagnostic Value of Insulinoma-Associated Protein 1 (INSM1) and Comparison With Established Neuroendocrine Markers in Pulmonary Cancers. Archives of pathology & laboratory medicine 50 31913660
2010 Fertility-conserving surgery for young women with stage IA1 cervical cancer: safety and access. Obstetrics and gynecology 48 20177290
2009 Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest. The Journal of biological chemistry 47 19124461
2002 The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein. Genomics 47 12079283
2020 Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin. Endocrine pathology 46 32813226
2009 Insm1 (IA-1) is an essential component of the regulatory network that specifies monoaminergic neuronal phenotypes in the vertebrate hindbrain. Development (Cambridge, England) 46 19542360
1999 Stage IA1 cervical adenocarcinoma: definition and treatment. Obstetrics and gynecology 46 9932559
2015 Insm1 controls the differentiation of pulmonary neuroendocrine cells by repressing Hes1. Developmental biology 45 26453796
2013 Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors. Development (Cambridge, England) 45 24227653
2003 The clinical outcome of patients with stage Ia1 and Ia2 squamous cell carcinoma of the uterine cervix: a Cooperation Task Force (CTF) study. European journal of gynaecological oncology 44 14658592
2011 Insm1 promotes the transition of olfactory progenitors from apical and proliferative to basal, terminally dividing and neuronogenic. Neural development 43 21284846
2008 An integrated approach identifies Nhlh1 and Insm1 as Sonic Hedgehog-regulated genes in developing cerebellum and medulloblastoma. Neoplasia (New York, N.Y.) 43 18231642
2019 Function and Transcriptional Regulation of Bovine TORC2 Gene in Adipocytes: Roles of C/EBP, XBP1, INSM1 and ZNF263. International journal of molecular sciences 42 31487963
1991 Xenobiotic induction of P-450 PB-4 (IIB1) and P-450c (IA1) and associated monooxygenase activities in primary cultures of adult rat hepatocytes. Xenobiotica; the fate of foreign compounds in biological systems 42 1788977
2020 Insulinoma-associated Protein 1 (INSM1) in Thoracic Tumors is Less Sensitive but More Specific Compared With Synaptophysin, Chromogranin A, and CD56. Applied immunohistochemistry & molecular morphology : AIMM 41 30358615
2015 Insm1 promotes neurogenic proliferation in delaminated otic progenitors. Mechanisms of development 41 26545349
1991 Induction, regulation and messenger half-life of cytochromes P450 IA1, IA2 and IIIA6 in primary cultures of rabbit hepatocytes. CYP 1A1, 1A2 and 3A6 chromosome location in the rabbit and evidence that post-transcriptional control of gene IA2 does not involve mRNA stabilization. European journal of biochemistry 39 1889414
2020 INSM1 expression in a subset of thoracic malignancies and small round cell tumors: rare potential pitfalls for small cell carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 38 32203089
2000 Prospective management of stage IA(1) cervical adenocarcinoma by conization alone to preserve fertility: a preliminary report. Gynecologic oncology 38 10926806
2021 INSM1, a Novel Biomarker for Detection of Neuroendocrine Neoplasms: Cytopathologists' View. Diagnostics (Basel, Switzerland) 36 34943408
2002 Expression of a novel zinc-finger cDNA, IA-1, is associated with rat AR42J cells differentiation into insulin-positive cells. Pancreas 31 11854618
2021 Reciprocal YAP1 loss and INSM1 expression in neuroendocrine prostate cancer. The Journal of pathology 30 34431104
2002 Comparison of activities dependent on glutathione S-transferase and cytochrome P-450 IA1 in cultured keratinocytes and reconstructed epidermal models. Skin pharmacology and applied skin physiology 30 12476009
2018 Sonic hedgehog signaling pathway promotes INSM1 transcription factor in neuroendocrine lung cancer. Cellular signalling 29 29501727
2020 Insulinoma-associated protein 1 (INSM1): a potential biomarker and therapeutic target for neuroendocrine tumors. Cellular oncology (Dordrecht, Netherlands) 28 32219703
2019 Alleles of Insm1 determine whether RIP1-Tag2 mice produce insulinomas or nonfunctioning pancreatic neuroendocrine tumors. Oncogenesis 28 30796198
1993 Hepatic cellular distribution of cytochrome P-450 IA1 in rainbow trout (Oncorhynchus mykiss): an immunohisto- and cytochemical study. Cancer research 28 8339279
2020 Expression of novel neuroendocrine marker insulinoma-associated protein 1 (INSM1) in genitourinary high-grade neuroendocrine carcinomas: An immunohistochemical study with specificity analysis and comparison to chromogranin, synaptophysin, and CD56. Pathology, research and practice 27 32381384
2019 Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites. Endocrine pathology 27 30523500
1994 Genomic organization, 5'-upstream sequence, and chromosomal localization of an insulinoma-associated intronless gene, IA-1. The Journal of biological chemistry 27 8188699
2021 INSM1 Is Less Sensitive But More Specific Than Synaptophysin in Gynecologic High-grade Neuroendocrine Carcinomas: An Immunohistochemical Study of 75 Cases With Specificity Test and Literature Review. The American journal of surgical pathology 26 33264139
2009 Conization using electrosurgical conization and cold coagulation for international federation of gynecology and obstetrics stage IA1 squamous cell carcinomas of the uterine cervix. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 26 19407568
2019 A new immunohistochemical marker, insulinoma-associated protein 1 (INSM1), for Merkel cell carcinoma: Evaluation of 24 cases. Annals of diagnostic pathology 25 31031215
2020 Insulinoma-associated protein 1 (INSM1) is a robust marker for identifying and grading pancreatic neuroendocrine tumors. Cancer cytopathology 22 31977134
2008 Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription. The Journal of endocrinology 22 18417529
2003 Stage Ia1 cervical squamous cell carcinoma: conservative management after laser conization with positive margins. Gynecologic oncology 22 12893205
2020 Silencing SCAMP1-TV2 Inhibited the Malignant Biological Behaviors of Breast Cancer Cells by Interaction With PUM2 to Facilitate INSM1 mRNA Degradation. Frontiers in oncology 21 32670859
2012 Functional role of an islet transcription factor, INSM1/IA-1, on pancreatic acinar cell trans-differentiation. Journal of cellular physiology 21 21830214
2007 Neurogenin 3 recruits CBP co-activator to facilitate histone H3/H4 acetylation in the target gene INSM1. FEBS letters 21 17300785
2021 INSM1 Expression in Breast Neoplasms with Neuroedocrine Features. Endocrine pathology 20 34008122
2018 CD10, TDAG51, CK20, AR, INSM1, and Nestin Expression in the Differential Diagnosis of Trichoblastoma and Basal Cell Carcinoma. International journal of surgical pathology 20 29938548
2018 Triple marker composed of p16, CD56, and TTF1 shows higher sensitivity than INSM1 for diagnosis of pulmonary small cell carcinoma: proposal for a rational immunohistochemical algorithm for diagnosis of small cell carcinoma in small biopsy and cytology specimens. Human pathology 20 30385371
1991 Application of a cytochrome P-450 IA1-ELISA in environmental monitoring and toxicological testing of fish. Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology 20 1677846
2018 INSM1 Expression Is Frequent in Primary Central Nervous System Neoplasms but Not in the Adult Brain Parenchyma. Journal of neuropathology and experimental neurology 19 29490065
2006 Expression of two insm1-like genes in the developing zebrafish nervous system. Gene expression patterns : GEP 19 16487754
2022 Insm1-expressing neurons and secretory cells develop from a common pool of progenitors in the sea anemone Nematostella vectensis. Science advances 18 35442742
2015 INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma. Oncotarget 18 26456864
2014 Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction. Cellular signalling 18 24407176
2024 Pro-inflammatory activity of Cutibacterium acnes phylotype IA1 and extracellular vesicles: An in vitro study. Experimental dermatology 17 39113601
2023 Epistatic genetic interactions between Insm1 and Ikzf2 during cochlear outer hair cell development. Cell reports 17 37171961
2021 Cross-talk among MEN1, p53 and Notch regulates the proliferation of pancreatic neuroendocrine tumor cells by modulating INSM1 expression and subcellular localization. Neoplasia (New York, N.Y.) 16 34352404
2020 Insulinoma-associated protein 1 (INSM-1) expression in medullary thyroid carcinoma FNA: a multi-institutional study. Journal of the American Society of Cytopathology 16 32197966
2020 Conditional survival rate estimates of lobectomy, segmentectomy and wedge resection for stage IA1 non-small cell lung cancer: A population-based study. Oncology letters 16 32724402
2003 Genetic effects of estrogen receptor alpha and collagen IA1 genes on the relationships of parathyroid hormone and 25 hydroxyvitamin D with bone mineral density in Caucasian women. Metabolism: clinical and experimental 16 14506618
2020 Insulinoma-associated protein 1 (INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective. Virchows Archiv : an international journal of pathology 15 33025295
2019 INSM1 Expression in Peripheral Neuroblastic Tumors and Other Embryonal Neoplasms. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 15 30975032
2022 Utility of Insulinoma-Associated Protein 1 (INSM1) and Mucin 2 (MUC2) Immunohistochemistry in the Distinction of Endocrine Mucin-Producing Sweat Gland Carcinoma From Morphologic Mimics. The American Journal of dermatopathology 14 34086646
2022 Insulinoma-associated-1 (INSM1) expression in thymic squamous cell carcinoma. Virchows Archiv : an international journal of pathology 14 36305944
2021 Next-generation sequencing analysis suggests varied multistep mutational pathogenesis for endocrine mucin-producing sweat gland carcinoma with comments on INSM1 and MUC2 suggesting a conjunctival origin. Journal of the American Academy of Dermatology 14 33515627
2020 Insulinoma-associated Protein 1 (INSM1) Expression in Small Cell Neuroendocrine Carcinoma of the Urinary Tract. Applied immunohistochemistry & molecular morphology : AIMM 14 31876605
2023 Comparison of INSM1 immunostaining with established neuroendocrine markers synaptophysin and chromogranin A in over 14,000 neuroendocrine and non-neuroendocrine tumors. Molecular and cellular endocrinology 13 37951531
2022 Expression of novel neuroendocrine markers in breast carcinomas: a study of INSM1, ASCL1, and POU2F3. Human pathology 13 35690220
2021 Insulinoma-associated protein 1(INSM1) is a superior marker for the diagnosis of gastroenteropancreatic neuroendoerine neoplasms: a meta-analysis. Endocrine 13 34021851
2020 Comparative performance of insulinoma-associated protein 1 (INSM1) and routine immunohistochemical markers of neuroendocrine differentiation in the diagnosis of endocrine mucin-producing sweat gland carcinoma. Journal of cutaneous pathology 13 32745280
2014 Fascin expression in cervical normal squamous epithelium, cervical intraepithelial neoplasia, and superficially invasive (stage IA1) squamous carcinoma of the cervix. Pathology 13 24977742
2010 Repeat surgery in patients with cervical cancer stage FIGO IA1: a series of 156 cases and a review of the literature. Anticancer research 13 20332471
2009 INSM1 promoter-driven adenoviral herpes simplex virus thymidine kinase cancer gene therapy for the treatment of primitive neuroectodermal tumors. Human gene therapy 13 19604042
2008 Xenopus zinc finger transcription factor IA1 (Insm1) expression marks anteroventral noradrenergic neuron progenitors in Xenopus embryos. Developmental dynamics : an official publication of the American Association of Anatomists 13 18627098
1991 Electron microscopic identification of the intracellular secretion pathway of human G-CSF in a human tumor cell line: a comparative study with a Chinese hamster ovary cell line (IA1-7) transfected with human G-CSF cDNA. Experimental hematology 13 1714402
2023 Insm1 regulates mTEC development and immune tolerance. Cellular & molecular immunology 12 37990032
2021 Diagnostic Utility of INSM1 in Medullary Thyroid Carcinoma. International journal of surgical pathology 12 33650906
2021 INSM1 Expression in Angiosarcoma. American journal of clinical pathology 11 33210141

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