Affinage

LZTS1

Leucine zipper putative tumor suppressor 1 · UniProt Q9Y250

Length
596 aa
Mass
66.6 kDa
Annotated
2026-06-10
29 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LZTS1 (FEZ1) is a leucine-zipper protein that associates with microtubule components and functions as a mitotic regulator and context-dependent tumor modulator (PMID:11504921, PMID:17349584). Mechanistically, LZTS1 stabilizes CDC25C during M phase: in Lzts1-knockout fibroblasts CDC25C is degraded prematurely, lowering CDK1 activity, accelerating mitotic progression, conferring resistance to taxol- and nocodazole-induced arrest, and producing chromosome mis-segregation, while Lzts1 loss raises spontaneous and carcinogen-induced cancer incidence in mice (PMID:17349584). LZTS1 interacts with CDK1 at late S-G2/M, is hyperphosphorylated by PKA during the cell cycle, and its re-expression in deficient cancer cells restores accumulation at late S-G2/M and suppresses tumorigenicity (PMID:11504921). This CDC25C-CDK1 axis underlies LZTS1-dependent microtubule-drug responses, including docetaxel sensitivity in prostate cancer and paclitaxel sensitivity in breast cancer (PMID:24525428). In neural development, microtubule-associated Lzts1—transcriptionally activated by HoxB cluster genes and tuned by Hes1—drives neuronal delamination by remodeling apical junctional organization and governs radial glial division modes, including generation of outer radial glia (PMID:31239441, PMID:33472847). In cancer signaling LZTS1 modulates PI3K/AKT and Hippo pathways, and is silenced by lncRNA-directed EZH2/DNMT promoter methylation and by direct miRNA targeting (miR-135b, miR-214, miR-762) (PMID:33637680, PMID:35958482, PMID:23695671). The directionality of LZTS1's effect on AKT signaling and proliferation is context-dependent: re-expression suppresses AKT-mTOR and growth in colorectal and hepatocellular carcinoma (PMID:25667121, PMID:26653561), whereas in other colorectal and gastric settings LZTS1 loss or its modulation correlates with reduced AKT activity and EMT suppression (PMID:39023696, PMID:35958482).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 High

    Established LZTS1 as a cell-cycle-associated protein by showing it binds CDK1 at late S-G2/M, is PKA-phosphorylated, associates with microtubules, and suppresses tumorigenicity when restored, defining a candidate mitotic regulator and tumor suppressor.

    Evidence Reciprocal Co-IP, kinase assay, flow cytometry, and tumorigenicity assays in cancer cell lines

    PMID:11504921

    Open questions at the time
    • Did not define the molecular substrate or downstream effector of LZTS1 in mitosis
    • PKA phosphorylation sites and their functional consequence not mapped
  2. 2007 High

    Placed LZTS1 upstream of the CDC25C-CDK1 axis by showing that genetic loss destabilizes CDC25C, lowers CDK1 activity, accelerates mitosis with chromosome mis-segregation, and increases cancer incidence in vivo.

    Evidence Lzts1-knockout MEFs, Western blot, drug-induced arrest assays, chromosome segregation analysis, and in vivo carcinogenesis

    PMID:17349584

    Open questions at the time
    • Molecular mechanism by which LZTS1 protects CDC25C from degradation not resolved
    • Direct versus indirect interaction with CDC25C not distinguished
  3. 2013 Medium

    Connected LZTS1 loss to metastasis by showing miR-135b directly targets its 3'UTR to enhance invasion in lung cancer, with rescue on miR-135b inhibition.

    Evidence 3'UTR reporter assay, miR overexpression/antagomir, invasion assays, orthotopic mouse model

    PMID:23695671

    Open questions at the time
    • miR-135b is multi-target, so LZTS1's specific contribution to the phenotype is partial
    • Did not define downstream signaling restored by LZTS1
  4. 2014 Medium

    Extended the miRNA-silencing model to osteosarcoma (miR-214) and linked LZTS1-CDC25C to acquired docetaxel resistance in prostate cancer, nominating CDC25C/CHEK1/PLK1 as therapeutic vulnerabilities in resistant cells.

    Evidence Dual-luciferase 3'UTR assay with rescue (osteosarcoma); siRNA knockdown, drug-sensitivity and inhibitor assays, methylation analysis (prostate)

    PMID:24525428 PMID:24802407

    Open questions at the time
    • Mechanism linking LZTS1-CDC25C to the resistant phenotype only inferred pharmacologically
    • Single-lab findings per cancer type
  5. 2015 Medium

    Defined LZTS1 as a negative regulator of PI3K/AKT-mTOR signaling, with re-expression arresting cells at G2/M, raising CDC25C, and suppressing growth in colorectal and hepatocellular carcinoma.

    Evidence Gain- and loss-of-function in CRC and HCC cells, Western blot for AKT/mTOR and CDC25C, cell-cycle analysis, xenografts, PI3K-inhibitor comparator

    PMID:25667121 PMID:26653561

    Open questions at the time
    • Whether AKT suppression is direct or secondary to cell-cycle arrest unresolved
    • No biochemical link between LZTS1 and PI3K/AKT components
  6. 2019 High

    Revealed a developmental function distinct from cell-cycle control: microtubule-associated Lzts1, dosed by Hes1, drives neuronal delamination via apical junctional remodeling and dictates radial glial division mode and neocortical expansion.

    Evidence In utero/in ovo electroporation, live imaging, gain- and loss-of-function in mouse and ferret, junctional immunostaining

    PMID:31239441

    Open questions at the time
    • Molecular mechanism linking Lzts1 to specific junctional proteins not delineated
    • Relationship between developmental role and CDC25C-CDK1 mitotic role not integrated
  7. 2021 Medium

    Identified upstream regulators of LZTS1 expression: HoxB genes transcriptionally activate it in the neural tube, while a lncRNA (Lnc-LALC) recruits EZH2/DNMTs to methylate and silence its promoter in colorectal cancer.

    Evidence In ovo electroporation and target identification (HoxB); RIP, ChIP, methylation-specific PCR, rescue, and metastasis model (Lnc-LALC)

    PMID:33472847 PMID:33637680

    Open questions at the time
    • Direct transcription-factor binding of HoxB to the LZTS1 promoter not fully resolved
    • Single-lab, single-model epigenetic silencing mechanism
  8. 2022 Medium

    Probed LZTS1's effect on PI3K/AKT and Hippo signaling across tumor types and microtubule-drug response, yielding context-dependent and partly opposing directionality of its proliferative role.

    Evidence miR-762 luciferase assay and pathway Western blots (gastric); bidirectional OE/KD with EMT markers (CRC); paclitaxel sensitization xenografts (breast)

    PMID:35500500 PMID:35958482 PMID:39023696

    Open questions at the time
    • The opposing oncogenic vs tumor-suppressor roles reported in colorectal cancer are unreconciled
    • Molecular basis for LZTS1's paclitaxel sensitization not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which LZTS1 stabilizes CDC25C and the molecular basis for its context-dependent, sometimes opposing, effects on PI3K/AKT signaling across cancers remain unresolved.
  • No structural or domain-level model for LZTS1-CDC25C or LZTS1-CDK1 interaction
  • No reconciliation of tumor-suppressor versus oncogenic roles in colorectal cancer
  • Direct effectors linking LZTS1 to apical junctional proteins unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2
Partners
CDC25CCDK1

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 LZTS1 (FEZ1) protein is hyperphosphorylated by cAMP-dependent kinase (PKA) during cell-cycle progression, associates with microtubule components, and interacts with p34(cdc2)/CDK1 at late S-G2/M stage in vivo; its introduction into Fez1/Lzts1-negative cancer cells suppresses tumorigenicity and causes accumulation of cells at late S-G2/M, establishing a role in mitotic regulation. Co-immunoprecipitation, cell cycle analysis (flow cytometry), kinase assay, colony formation/tumorigenicity assay in cancer cells Proceedings of the National Academy of Sciences of the United States of America High 11504921
2007 In Lzts1-knockout mouse embryo fibroblasts, Cdc25C degradation is increased during M phase, resulting in decreased CDK1 activity, accelerated mitotic progression, resistance to taxol- and nocodazole-induced M phase arrest, and improper chromosome segregation; Lzts1 deficiency increases incidence of spontaneous and carcinogen-induced cancers in mice, placing LZTS1 upstream of Cdc25C-CDK1 axis in mitotic control. Lzts1 knockout mouse (MEF studies), Western blot for Cdc25C and CDK1 activity, cell cycle analysis, drug-induced arrest assays, chromosomal segregation analysis, in vivo carcinogenesis Cancer cell High 17349584
2014 LZTS1 regulates CDC25C in the context of docetaxel resistance in prostate cancer; knockdown of LZTS1 confers a resistant phenotype, and pharmacological inhibition of CDC25C (a LZTS1 partner) with NSC663284 specifically kills docetaxel-resistant cells; inhibition of CHEK1 and PLK1, which regulate CDC25C, also induces growth arrest and death in resistant cells. siRNA knockdown, drug sensitivity assays, inhibitor treatment, gene expression microarray, promoter methylation analysis Oncotarget Medium 24525428
2015 Re-expression of LZTS1 in colorectal cancer cells inhibits proliferation and tumor growth in part by suppressing AKT-mTOR signaling, leading to downregulation of p27Kip and upregulation of cyclin D1; conversely, LZTS1 silencing promotes proliferation. LZTS1 overexpression and siRNA knockdown in CRC cells, Western blot for AKT/mTOR pathway components, cell proliferation assay, in vivo xenograft Cancer letters Medium 25667121
2015 LZTS1 re-expression in hepatocellular carcinoma cells decreases proliferation, arrests cells at G2/M, significantly increases Cdc25C expression, and suppresses PI3K/AKT pathway activity (decreased phospho-Akt S473 and T308), placing LZTS1 as a negative regulator of the PI3K/AKT pathway. LZTS1 lentiviral overexpression in HCC cells, flow cytometry cell cycle analysis, Western blot for Cdc25C, CDK1, cyclin D1, phospho-Akt; comparison with PI3K inhibitor LY294002 Biomedicine & pharmacotherapy Medium 26653561
2019 Lzts1, associated with microtubule components, promotes neuronal delamination from the apical surface in the developing cerebral cortex by altering apical junctional organization; in apical radial glia, variable Lzts1 levels (regulated by Hes1 expression) determine cell behavior—planar division, oblique divisions generating outer radial glial cells (oRGs), and mitotic somal translocation. Loss-of-function of lzts1 impairs all cell departure processes. In utero electroporation, live imaging, loss-of-function (shRNA/dominant-negative), gain-of-function in mouse and ferret cortex; immunostaining for junctional proteins Nature communications High 31239441
2021 HoxB cluster genes (HoxB4, HoxB8, HoxB9) transcriptionally activate Lzts1 expression in the trunk neural tube; Lzts1 expressed in the intermediate zone controls neuronal delamination, as shown by gain- and loss-of-function experiments in chicken embryo. In ovo electroporation (gain- and loss-of-function), qRT-PCR, immunostaining, identification of HoxB8 downstream targets Development (Cambridge, England) Medium 33472847
2021 The lncRNA Lnc-LALC recruits DNA methyltransferases (DNMTs) to the LZTS1 promoter by binding EZH2, causing DNMT-mediated DNA methylation and silencing of LZTS1 expression, thereby enhancing CRC cell metastasis in vitro and in vivo. RNA immunoprecipitation, ChIP assay for DNMT and EZH2 at LZTS1 promoter, methylation-specific PCR, LZTS1 rescue experiments, in vitro invasion/migration assays, mouse metastasis model Cell death & disease Medium 33637680
2022 LZTS1 overexpression in colorectal cancer cells upregulates AKT activity and promotes EMT (increased N-cadherin, decreased E-cadherin, decreased PTEN); depletion of LZTS1 represses proliferation and migration, indicating an oncogenic role for LZTS1 in CRC via PI3K-AKT and EMT pathways. LZTS1 overexpression and knockdown in CRC cells, Western blot for AKT phosphorylation and EMT markers, cell proliferation and migration assays, tissue microarray, bioinformatic correlation analysis Journal of cellular and molecular medicine Medium 39023696
2022 miR-762 directly targets LZTS1 (confirmed by dual-luciferase reporter assay); miR-762-mediated suppression of LZTS1 activates PI3K/AKT signaling and inhibits the Hippo pathway in gastric cancer cells, promoting proliferation and invasion; LZTS1 overexpression reverses these effects. Dual-luciferase reporter assay, qRT-PCR, Western blot for PI3K/AKT and Hippo pathway components, CCK-8, transwell, flow cytometry American journal of translational research Medium 35958482
2022 LZTS1 overexpression sensitizes breast cancer cells to paclitaxel, enhancing paclitaxel-induced cell cycle arrest and apoptosis in vitro and in xenograft models, suggesting LZTS1 influences microtubule-dependent drug response. LZTS1 overexpression in MDA-MB-231 cells, flow cytometry (cell cycle/apoptosis), cell proliferation assays, xenograft drug-sensitivity model, immunohistochemistry Pathology, research and practice Low 35500500
2013 miR-135b directly targets LZTS1 (among other Hippo pathway components) in non-small-cell lung cancer, suppressing LZTS1 expression to enhance cancer cell invasion and migration; specific inhibition of miR-135b restores LZTS1 levels and suppresses metastasis in vivo. Reporter assay (miR-135b targeting LZTS1 3'UTR), miR-135b overexpression and sponge/antagomir inhibition, invasion/migration assays, orthotopic mouse model Nature communications Medium 23695671
2014 miR-214 directly binds the 3'-UTR of LZTS1 mRNA (confirmed by reporter assay) and suppresses LZTS1 at both mRNA and protein levels in osteosarcoma; miR-214-driven proliferation, invasion, and tumor growth are reversed by LZTS1 overexpression. Dual-luciferase 3'UTR reporter assay, miR-214 overexpression/inhibition, LZTS1 rescue, in vitro proliferation/invasion assays, nude mouse xenograft Biochemical and biophysical research communications Medium 24802407

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. Nature communications 254 23695671
2001 FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis. Proceedings of the National Academy of Sciences of the United States of America 92 11504921
2004 Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. Cancer letters 65 15922864
2007 Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development. Cancer cell 58 17349584
2001 Fez1/lzts1 alterations in gastric carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 47 11410489
2001 Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22. Oncogene 47 11464283
2014 miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1. Biochemical and biophysical research communications 44 24802407
2002 FEZ1/LZTS1 is down-regulated in high-grade bladder cancer, and its restoration suppresses tumorigenicity in transitional cell carcinoma cells. The American journal of pathology 44 11943719
2005 Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer. Cancer research 37 15735004
2021 Long non-coding RNA Lnc-LALC facilitates colorectal cancer liver metastasis via epigenetically silencing LZTS1. Cell death & disease 36 33637680
2015 The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway. Cancer letters 34 25667121
2008 Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis. Breast cancer research and treatment 34 18686028
2018 miR-1207-5p regulates the sensitivity of triple-negative breast cancer cells to Taxol treatment via the suppression of LZTS1 expression. Oncology letters 31 30655858
2002 Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures. Clinical cancer research : an official journal of the American Association for Cancer Research 31 12114433
2019 Lzts1 controls both neuronal delamination and outer radial glial-like cell generation during mammalian cerebral development. Nature communications 30 31239441
2014 Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer. Oncotarget 30 24525428
2003 Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas. International journal of oncology 26 12851677
2013 Cytosine 5-Hydroxymethylation of the LZTS1 Gene Is Reduced in Breast Cancer. Translational oncology 23 24466374
2023 LncRNA LZTS1-AS1 induces proliferation, metastasis and inhibits autophagy of pancreatic cancer cells through the miR-532 /TWIST1 signaling pathway. Cancer cell international 20 37403096
2015 Loss of Leucine Zipper Putative Tumor Suppressor 1 (LZTS1) Expression Contributes to Lymph Node Metastasis of Breast Invasive Micropapillary Carcinoma. Pathology oncology research : POR 19 25813822
2015 The tumor-suppressor gene LZTS1 suppresses hepatocellular carcinoma proliferation by impairing PI3K/Akt pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 26653561
2007 Fez1/Lzts1 a new mitotic regulator implicated in cancer development. Cell division 18 17718912
2008 Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis. Carcinogenesis 16 18192690
2002 Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer genetics and cytogenetics 16 12377406
2021 HoxB genes regulate neuronal delamination in the trunk neural tube by controlling the expression of Lzts1. Development (Cambridge, England) 11 33472847
2022 MiR-762 regulates the activation of PI3K/AKT and Hippo pathways involved in the development of gastric cancer by targeting LZTS1. American journal of translational research 7 35958482
2006 Mutation and expression analysis of LZTS1 in ovarian cancer. Cancer letters 5 15876481
2024 Unveiling the oncogenic role of LZTS1 in colorectal cancer. Journal of cellular and molecular medicine 4 39023696
2022 Increased LZTS1 expression is associated with a good response to paclitaxel-based chemotherapy in breast cancer. Pathology, research and practice 1 35500500

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