Affinage

KISS1

Metastasis-suppressor KiSS-1 · UniProt Q15726

Length
138 aa
Mass
14.7 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KISS1 encodes a secreted precursor protein that is processed by furin into kisspeptin peptides (including kisspeptin-54/metastin and kisspeptin-10), which function as endogenous ligands for the G-protein-coupled receptor GPR54/KISS1R to regulate two major biological processes: suppression of tumor metastasis and control of reproductive neuroendocrine function (PMID:11385580, PMID:24454770). In cancer, secreted kisspeptins suppress metastasis by inhibiting cell motility and invasion through PKCα, RhoA/NF-κB, and Rho GTPase signaling pathways, and by promoting mitochondrial biogenesis via PGC1α/NRF1 to reverse the Warburg effect; matrix metalloproteinases (MMP-2, MMP-9, MT-MMPs) inactivate kisspeptins by cleaving a critical peptide bond (PMID:16283480, PMID:19533666, PMID:24351292, PMID:12879005). In the hypothalamus, Kiss1 neurons function as essential pacemaker integrators of GnRH pulsatility, with Kiss1 transcription governed by a combinatorial code of transcription factors (TTF1, CUX1, EAP1, YY1, NHLH2, TCF21, ESR2) and epigenetic regulators including the SIRT1–Polycomb complex whose eviction at puberty enables reproductive maturation (PMID:21672609, PMID:34494548, PMID:30305620, PMID:25582792). Inactivating KISS1 mutations cause failure of pubertal progression in humans, while gain-of-function variants are associated with central precocious puberty (PMID:22335740, PMID:20237166).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    The identity of the endogenous ligand for the orphan receptor GPR54 was unknown; isolation of kisspeptin-54 from placenta and demonstration of its receptor binding established the KISS1–GPR54 signaling axis and its capacity to suppress metastasis through inhibition of chemotaxis and invasion.

    Evidence Expression cloning from human placenta, peptide characterization, receptor binding assays in CHO cells, and in vivo melanoma metastasis model

    PMID:11385580

    Open questions at the time
    • Downstream signaling pathways mediating metastasis suppression not yet defined
    • Whether KISS1 suppresses metastasis in GPR54-negative contexts was unresolved
    • The enzyme(s) responsible for processing KISS1 precursor into active kisspeptins were unknown
  2. 2003 High

    The question of how kisspeptin activity is terminated in vivo was answered by identifying MMP-2, MMP-9, and membrane-type MMPs as inactivating proteases that cleave kisspeptin at Gly118-Leu119, abolishing ligand activity and linking the tumor MMP milieu to escape from KISS1-mediated suppression.

    Evidence Co-immunoprecipitation of KISS1 with pro-MMP-2/9; in vitro cleavage assays; cell migration assays with MMP inhibitors

    PMID:12879005

    Open questions at the time
    • In vivo relevance of MMP-mediated kisspeptin inactivation in metastatic progression not demonstrated
    • Whether MMP cleavage regulates kisspeptin in the hypothalamic context was unknown
  3. 2005 Medium

    The intracellular signaling mechanism downstream of KISS1 in metastasis suppression was partially elucidated by identifying PKCα as a key effector whose inhibition mediates KISS1-dependent suppression of ovarian cancer cell migration.

    Evidence KISS1 overexpression in SKOV3 cells; PKC activator and PKCα shRNA epistasis; migration and in vivo metastasis assays

    PMID:16283480

    Open questions at the time
    • Whether PKCα is a direct target of KISS1R signaling or an indirect effector was not established
    • Generalizability to other tumor types was untested
  4. 2007 High

    Whether KISS1 must be secreted to suppress metastasis was directly tested; deletion of the signal sequence abolished kisspeptin secretion, calcium signaling, and in vivo metastasis suppression, while activity in GPR54-negative melanoma cells suggested an additional receptor or paracrine mechanism.

    Evidence FLAG-tagged KISS1 ± signal sequence in melanoma cells; ELISA, calcium mobilization, in vivo EGFP-labeled metastasis model

    PMID:17312308

    Open questions at the time
    • The putative alternative KISS1 receptor in GPR54-negative cells remains unidentified
    • Mechanism of paracrine signaling not defined
  5. 2009 Medium

    The downstream signaling pathways were further resolved: kisspeptin-10 suppresses NF-κB via RhoA inhibition in breast cancer and inhibits angiogenesis by blocking Sp1/VEGF expression and c-Src/FAK/Rac/Cdc42 activation in endothelial cells, broadening the anti-metastatic mechanism beyond cell-autonomous motility suppression.

    Evidence NF-κB reporter and RhoA activation assays in breast cancer cells; HUVEC migration/invasion/tube formation; CAM and corneal micropocket angiogenesis assays

    PMID:19533666 PMID:19671799

    Open questions at the time
    • Whether RhoA inhibition and NF-κB suppression are direct GPR54-coupled events was not established
    • In vivo validation of anti-angiogenic activity in spontaneous tumor models lacking
  6. 2011 High

    The transcriptional regulation of KISS1 was systematically dissected: TTF1 and CUX1-p200 activate the KISS1 promoter while EAP1, YY1, and CUX1-p110 repress it; additionally, TCF21 directly binds and activates the KISS1 promoter, with TCF21 silencing by DNA methylation in metastatic melanoma providing an epigenetic mechanism for KISS1 loss.

    Evidence TSS mapping by RACE-PCR; ChIP for TF recruitment; luciferase reporter assays in 293MSR and GT1-7 cells; DNA methylation analysis of TCF21 in melanoma

    PMID:21672609 PMID:21771727

    Open questions at the time
    • Relative contributions of individual TFs to Kiss1 expression in vivo not quantified
    • How TCF21 methylation is regulated during metastatic progression was not addressed
  7. 2011 High

    Electrophysiological characterization of genetically identified arcuate Kiss1 neurons revealed intrinsic pacemaker properties (h-type and T-type calcium currents) and NMDA-induced bursting, establishing the biophysical basis for pulsatile kisspeptin release governing GnRH pulsatility.

    Evidence Whole-cell patch clamp of GFP-labeled ARC Kiss1 neurons in Kiss1-CreGFP mice; single-cell RT-PCR for HCN1-4 and CaV3.1

    PMID:21933870

    Open questions at the time
    • Whether pacemaker activity directly drives pulsatile LH secretion was not causally tested
    • Ion channel contributions were not individually perturbed
  8. 2012 High

    The human genetic requirement for KISS1 in reproduction was established when an inactivating KISS1 missense mutation was found to cause failure of pubertal progression, complementing earlier identification of gain-of-function variants in precocious puberty.

    Evidence Sequencing of consanguineous family with hypogonadotropic hypogonadism; in vitro functional assessment of mutant peptide; earlier P74S/H90D variants in CPP with stability assays

    PMID:20237166 PMID:22335740

    Open questions at the time
    • Genotype-phenotype spectrum across different KISS1 mutations incompletely characterized
    • Whether partial loss-of-function alleles cause milder reproductive phenotypes unknown
  9. 2013 Medium

    KISS1 was shown to reprogram cancer cell metabolism by promoting mitochondrial biogenesis through interaction with NRF1 and upregulation of PGC1α, reversing the Warburg effect and linking metastasis suppression to metabolic control.

    Evidence Mitochondrial mass quantification; metabolic flux analysis; KISS1-NRF1 interaction assays; shRNA rescue with KISS1 and PGC1α

    PMID:24351292

    Open questions at the time
    • Whether KISS1-NRF1 interaction is direct or mediated through a complex was not resolved
    • Metabolic reprogramming not confirmed in in vivo metastasis models
    • Relationship between metabolic shift and motility suppression not mechanistically linked
  10. 2013 High

    Estradiol modulation of Kiss1 neurons was shown to require ERα: conditional ERα deletion from Kiss1 neurons abolished estradiol-induced changes in AVPV/PeN Kiss1 neuron firing patterns and membrane properties, while KATP channels were identified as regulators of bimodal resting potential.

    Evidence Patch clamp of GFP-labeled Kiss1 neurons with conditional ERα knockout in hypothalamic slices

    PMID:23407940

    Open questions at the time
    • The signaling cascade from ERα to KATP channel modulation was not defined
    • Whether these electrophysiological changes directly control kisspeptin release was not measured
  11. 2014 High

    Furin was identified as the primary proprotein convertase responsible for processing the KISS1 precursor into active kisspeptin peptides, resolving the long-standing question of which enzyme generates bioactive kisspeptins.

    Evidence Furin shRNA (but not PCSK5/PCSK7) completely blocks KISS1 processing; proprotein convertase inhibitors confirm

    PMID:24454770

    Open questions at the time
    • Whether furin processes KISS1 in all physiological contexts (hypothalamus, placenta) was not tested
    • Subcellular site of furin-mediated processing not determined
  12. 2015 High

    Kiss1 knockout rats demonstrated that Kiss1 neurons are essential integrators of stimulatory neural inputs to GnRH neurons: pulsatile LH secretion was completely abolished, and major excitatory neurotransmitters (glutamate, norepinephrine) failed to stimulate LH without Kiss1.

    Evidence Kiss1 KO rat; serial blood sampling for LH pulses; pharmacological challenges with NMDA, norepinephrine, and kisspeptin

    PMID:25582792

    Open questions at the time
    • Whether residual reproductive function exists in aged Kiss1 KO animals was not assessed
    • Specific neural circuits mediating glutamate/NE input convergence on Kiss1 neurons were not mapped
  13. 2018 High

    The metabolic gating of puberty through Kiss1 was mechanistically resolved: SIRT1, a fuel-sensing deacetylase, cooperates with the Polycomb complex to epigenetically silence Kiss1 prepubertally; its eviction at puberty triggers a repressive-to-permissive chromatin switch, with nutritional status modulating the timing of this transition.

    Evidence ChIP for SIRT1 at Kiss1 promoter; SIRT1-Polycomb co-IP; conditional SIRT1 overexpression in Kiss1 neurons; nutritional manipulation experiments

    PMID:30305620

    Open questions at the time
    • The molecular trigger for SIRT1 eviction at puberty was not identified
    • Whether SIRT1-Polycomb regulation operates in AVPV Kiss1 neurons was not tested
  14. 2021 High

    NHLH2 was identified as a direct transcriptional activator of both KISS1 and TAC3 promoters in arcuate Kiss1 neurons; its conditional ablation causes male-specific puberty delay and impairs metabolic regulation of LH secretion, establishing NHLH2 as a transcriptional node linking metabolism and reproduction through Kiss1.

    Evidence Drop-Seq single-cell transcriptomics; ChIP for NHLH2 at KISS1/TAC3 promoters; Kiss1Cre:Nhlh2fl/fl conditional KO mice

    PMID:34494548

    Open questions at the time
    • Why the phenotype is male-specific despite Kiss1 importance in both sexes is unexplained
    • Whether NHLH2 interacts with other known Kiss1 promoter regulators was not tested
  15. 2022 Medium

    A miRNA-dependent regulatory layer was uncovered: Dicer ablation in Kiss1 neurons causes late-onset hypogonadotropic hypogonadism by derepressing Kiss1 transcriptional repressors (Mkrn3, Cbx7, Eap1), revealing that miRNAs normally maintain Kiss1 expression by silencing its repressors.

    Evidence Kiss1-Cre conditional Dicer KO mice; ISH for Kiss1 and repressor mRNAs; hormonal and reproductive phenotyping

    PMID:35945211

    Open questions at the time
    • Specific miRNAs targeting Mkrn3, Cbx7, and Eap1 were not identified
    • Why the phenotype is late-onset rather than developmental was not explained
    • Single genetic model without independent validation of individual miRNA contributions

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the putative alternative KISS1 receptor in GPR54-negative cells, the structural basis of kisspeptin–GPR54 signaling, and how the multiple transcriptional and epigenetic inputs to the Kiss1 promoter are hierarchically integrated in vivo to generate pulsatile kisspeptin output.
  • No alternative KISS1 receptor has been identified despite functional evidence
  • No structural model of kisspeptin-GPR54 complex exists in the timeline
  • How stress, metabolic, and hormonal signals converge on Kiss1 chromatin state in real time is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 2
Partners
ESR2FURINKISS1RMMP2MMP9NHLH2NRF1SIRT1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 KISS1 encodes a 54-amino acid C-terminally amidated peptide (metastin/kisspeptin-54) that acts as the endogenous ligand for the orphan G-protein-coupled receptor hOT7T175 (GPR54/KISS1R), isolated from human placenta by expression cloning. Expression cloning from human placenta cDNA library, peptide isolation and characterization, receptor binding assays, CHO cell transfection with hOT7T175 Nature High 11385580
2001 Metastin (kisspeptin-54) inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo, establishing a functional receptor-dependent metastasis suppression mechanism. In vitro chemotaxis/invasion assays with CHO cells transfected with hOT7T175; in vivo mouse melanoma metastasis model Nature High 11385580
2003 KISS1 protein forms a stable complex with pro-MMP-2 and pro-MMP-9; active MMP-2, MMP-9, MT1-MMP, MT3-MMP, and MT5-MMP cleave the Gly118-Leu119 peptide bond of full-length KISS1 and metastin decapeptide, abolishing its ligand activity. Expression cloning from human placenta cDNA library; co-immunoprecipitation; in vitro MMP cleavage assays; cell migration assays with MMP inhibitor Oncogene High 12879005
2003 Metastin decapeptide induces formation of focal adhesion and actin stress fibers in cells expressing GPR54/hOT7T175, establishing a downstream cytoskeletal signaling mechanism. Treatment of GPR54-expressing cells with metastin decapeptide and imaging of focal adhesion and actin stress fiber formation Oncogene Medium 12879005
2007 KISS1 secretion (via its signal sequence) is required for metastasis suppression; deletion of the signal sequence (ΔSS) abolishes kisspeptin secretion, calcium mobilization in GPR54-expressing cells, and in vivo metastasis suppression. Metastasis suppression in C8161.9 cells (which lack GPR54) suggests the existence of an additional KISS1 receptor or paracrine signaling mechanism. FLAG-tagged KISS1 constructs with/without signal sequence transfected into melanoma cells; ELISA for kisspeptin in conditioned medium; calcium mobilization assays in CHO-GPR54 cells; in vivo mouse metastasis model with EGFP-labeled cells Journal of the National Cancer Institute High 17312308
2005 KISS1 suppresses metastasis in ovarian cancer through inhibition of PKCα; activating PKC reverses ~80% of KiSS1-mediated inhibition of cell migration, and shRNA knockdown of PKCα restores KISS1 suppressive effects. KiSS1 overexpression in SKOV3 cells; PKC activator treatment; PKCα shRNA knockdown; cell migration assays; experimental mouse metastasis model Clinical & experimental metastasis Medium 16283480
2009 Kisspeptin-10 (Kp-10) inhibits tumor angiogenesis by suppressing Sp1-mediated VEGF expression and blocking activation of c-Src/FAK and Rac/Cdc42 (RhoGTPase) signaling pathways in HUVECs, inhibiting HUVEC migration, invasion, and tube formation. HUVEC functional assays (migration, invasion, tube formation); CAM assay; mouse corneal micropocket assay; promoter binding assays (Sp1/VEGF); signaling pathway analysis Cancer research Medium 19671799
2009 KiSS1 suppresses TNFα-induced NF-κB activation and breast cancer cell migration via inhibition of RhoA GTPase activation; both KiSS1 overexpression and KP-10 stimulation inhibit TNFα-induced NF-κB activity and RhoA activation. KiSS1 overexpression; KP-10 peptide stimulation; NF-κB reporter assays; RhoA activation assays; cell migration assays in breast cancer cells Journal of cellular biochemistry Medium 19533666
2011 TCF21 transcription factor directly binds the KISS1 promoter and enhances KISS1 gene expression through interaction with E12 (TCF3 isoform) and TCF12; epigenetic silencing of TCF21 by promoter hypermethylation in metastatic melanoma leads to loss of KISS1 expression. Chromatin immunoprecipitation (ChIP) at KISS1 promoter; co-immunoprecipitation of TCF21 with E12/TCF12; luciferase reporter assays; quantitative DNA methylation analysis; cell motility assays Carcinogenesis High 21771727
2011 WASF3 suppresses KISS1 transcription; knockdown of WASF3 upregulates KISS1, reduces NF-κB nuclear translocation and MMP-9 activity, and reduces invasion; subsequent KISS1 knockdown rescues the invasion phenotype, demonstrating WASF3 acts upstream of KISS1 in the NF-κB/MMP-9 invasion pathway. WASF3 shRNA knockdown; KISS1 luciferase reporter; IκBα/NF-κB subcellular fractionation; zymography for MMP-9; Transwell invasion assays International journal of cancer Medium 21544801
2013 KISS1 expression reverses the Warburg effect by enhancing mitochondrial biogenesis: KISS1-expressing cells have 30-50% more mitochondrial mass, increased PGC1α expression, and shift metabolism from aerobic glycolysis to oxidative phosphorylation; KISS1 directly interacts with NRF1 (a transcription factor for mitochondrial biogenesis), and effects are reversed by shRNA to KISS1 or PGC1α. Mitochondrial mass measurement; metabolic flux analysis; PGC1α and NRF1 expression analysis; KISS1-NRF1 interaction assays; shRNA to KISS1 and PGC1α Cancer research Medium 24351292
2014 Furin is the primary proprotein convertase responsible for processing full-length KISS1 into kisspeptin peptides; shRNA knockdown of furin (but not PCSK5 or PCSK7) completely blocks KISS1 processing, and broad proprotein convertase inhibitors (Dec-RVKR-CMK, α1-PDX) also block processing. Proprotein convertase inhibitor treatment; shRNA knockdown of furin, PCSK5, PCSK7; immunoblotting for KISS1 processing products in conditioned medium PloS one High 24454770
2011 Transcription of human KiSS1 is initiated at a single TSS located 153-156 bp upstream of the ATG; the KiSS1 promoter is activated by TTF1 and CUX1-p200, and repressed by EAP1, YY1, and CUX1-p110; all four transcription factors are recruited in vivo to the KiSS1 promoter and expressed in kisspeptin neurons. RACE-PCR to map TSS; luciferase promoter assays in 293 MSR and GT1-7 cells; chromatin immunoprecipitation (ChIP) for TF recruitment to KiSS1 promoter Molecular and cellular endocrinology High 21672609
2018 SIRT1, a fuel-sensing deacetylase expressed in hypothalamic Kiss1 neurons, epigenetically represses Kiss1 expression by interacting with the Polycomb silencing complex to decrease Kiss1 promoter activity; as puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a repressive-to-permissive chromatin switch. Undernutrition raises SIRT1 levels and delays puberty, while overnutrition accelerates SIRT1 eviction and advances puberty. ChIP for SIRT1 at Kiss1 promoter; SIRT1-Polycomb co-immunoprecipitation; conditional Kiss1-neuron specific SIRT1 overexpression via transgenesis and virogenetic ARC targeting; pharmacological SIRT1 activation; luciferase reporter assays Nature communications High 30305620
2015 Kiss1 neurons in the hypothalamic arcuate nucleus arise developmentally from POMC-expressing progenitors, establishing a developmental link between nutrient-sensing and reproductive neuropeptide-producing neurons. Embryonic and adult ribosome-tagging strategies combined in mice (TRAP); Cre-loxP lineage tracing from Pomc-expressing precursors The Journal of neuroscience Medium 25855171
2012 An inactivating missense mutation in KISS1 (within the mature kisspeptin peptide) causes failure of pubertal progression in humans, demonstrating that functional kisspeptin secretion is required for puberty and reproduction. Human genetic study in consanguineous family; sequencing of KISS1; in vitro functional assessment of mutant peptide The New England journal of medicine High 22335740
2010 KISS1 mutations (P74S and H90D) identified in children with idiopathic central precocious puberty; P74S variant confers greater resistance to serum degradation (in vitro degradation assays), suggesting increased kisspeptin stability as a mechanism for gain-of-function in puberty. KISS1 gene sequencing in CPP patients; in vitro inositol phosphate accumulation assays with mutant kp54; serum degradation stability assays with mutant vs. wild-type kp54 The Journal of clinical endocrinology and metabolism Medium 20237166
2015 Kiss1 KO rats show complete suppression of pulsatile LH secretion and absence of LH/FSH surges; major stimulatory neurotransmitters (glutamate/NMDA, norepinephrine) fail to stimulate LH in Kiss1 KO rats, establishing Kiss1 neurons as a hub integrating major stimulatory neural inputs to GnRH neurons. Kiss1 knockout rat generation; serial blood sampling for pulsatile LH measurement; pharmacological challenges (monosodium glutamate, NMDA, norepinephrine, kisspeptin); ovariectomy-induced LH surge assays Journal of neuroendocrinology High 25582792
2013 Kiss1 neurons in the AVPV/PeN exhibit a bimodal resting membrane potential influenced by KATP channels; estradiol shifts firing patterns of AVPV/PeN Kiss1 neurons and alters cell capacitance and spontaneous IPSC amplitude; these estradiol-induced changes require estrogen receptor α (ERα), as demonstrated by selective ERα deletion from Kiss1 neurons. Whole-cell and loose-attached patch clamp recordings of GFP-labeled Kiss1 neurons in hypothalamic slices; conditional ERα knockout in Kiss1 neurons; electrophysiological characterization The Journal of neuroscience High 23407940
2011 Arc Kiss1 neurons in female mice exhibit spontaneous pacemaker activity and express h-type (HCN1-4) and T-type calcium (CaV3.1) currents; NMDA induces bursting activity with depolarizing/hyperpolarizing oscillations, establishing molecular and electrophysiological properties consistent with pacemaker neurons. Kiss1-CreGFP knockin mouse; whole-cell patch clamp of GFP-labeled ARC Kiss1 neurons in hypothalamic slices; single-cell RT-PCR for HCN1-4 and CaV3.1 channel subtypes Endocrinology High 21933870
2014 Ghrelin receptor (GHSR) is co-expressed with ERα in ARC Kiss1 neurons; high estradiol levels increase GHSR mRNA expression and GHSR-ERα coexpression selectively in ARC Kiss1 neurons; ghrelin depolarizes 75% of ARC Kiss1 neurons in estradiol-treated vs. 22% in ovariectomized mice, demonstrating estradiol modulates ghrelin responsiveness of kisspeptin neurons. Dual in situ hybridization for GHSR and ERα; patch clamp electrophysiology of ARC Kiss1 neurons in response to ghrelin under different estradiol conditions; quantitative co-localization analysis American journal of physiology. Endocrinology and metabolism Medium 24473434
2013 Leptin signaling does not arise in Kiss1 neurons until after puberty completion; re-expression of LepR selectively in Kiss1 neurons of LepR-null mice fails to rescue puberty or fertility, and Kiss1-LepR coexpression is absent in prepubertal mice, demonstrated by Kiss1-hrGFP × LepR-Cre × R26-tdTomato reporter mice. Conditional LepR re-expression in Kiss1 neurons of LepR-null mice (Cre-loxP); Kiss1-hrGFP × LepR-Cre × R26-tdTomato reporter triple-transgenic mice; immunofluorescence coexpression analysis at prepubertal and adult stages PloS one High 23505551
2018 Gonadotropin-induced Kiss1 expression in ovarian granulosa cells depends on ESR2 (estrogen receptor-β); ESR2 binds the Kiss1 promoter and upstream/downstream enhancers (identified by ChIP and histone mark analysis); ESR2 phosphorylation by ERK2 and AP-1 factors (FOSL2, JUNB) synergistically activate Kiss1 promoter activity; ERE mutation within the promoter blocks ESR2-mediated activation. ChIP for ESR2 at Kiss1 promoter and enhancers; luciferase reporter assays with Kiss1 promoter constructs and ERE mutations; ESR2 overexpression; Esr2-null rat ovaries; MAPK/ERK2 phosphorylation analysis Endocrinology High 30277501
2021 Nhlh2 (a bHLH transcription factor enriched in Kiss1 neurons) directly binds and transactivates the KISS1 and TAC3 (NKB) promoters; conditional Nhlh2 ablation from Kiss1 neurons causes male-specific puberty delay with decreased arcuate Kiss1 expression, and impairs metabolic regulation of LH secretion and leptin response. Drop-Seq single-cell transcriptomics; in situ hybridization; JASPAR binding site analysis; in vitro luciferase assays with KISS1/TAC3 promoters; ChIP for NHLH2 at KISS1 and TAC3 promoters; Kiss1Cre:Nhlh2fl/fl conditional KO mice eLife High 34494548
2011 KISS1 full-length (with signal sequence) but not KISS1ΔSS (lacking signal sequence) re-sensitizes PC-3M prostate cancer cells to anoikis and suppresses cell motility and invasiveness, establishing secretion as required for KISS1 metastasis suppression in prostate cancer. KISS1 vs. KFMΔSS overexpression in PC-3M cells; anoikis assay; proliferation and apoptosis assays; motility and invasion assays The American journal of pathology Medium 22226740
2017 KiSS1 is a downstream target of canonical TGFβ/Smad2 signaling in triple-negative breast cancer cells; KiSS1 expression is required for TGFβ-induced invasion and MMP9 expression/activity; KP-10 promotes invasion through MAPK/Erk activation; a positive feedback loop exists between KiSS1 and p21 downstream of TGFβ. TGFβ stimulation of TNBC cells; KiSS1 shRNA knockdown; luciferase reporter; MMP9 zymography; MAPK/Erk inhibition; p234 peptide antagonist treatment Cellular signalling Medium 28988968
2011 Kiss1 receptor (Kiss1r) haploinsufficiency in MMTV-PyMT mice attenuates breast tumor initiation, growth, and lung metastasis; Kiss1r activation by Kisspeptin-10 stimulates RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway, and anchorage-independent growth is regulated dose-dependently by RhoA downstream of Kiss1r. Kiss1r heterozygous × MMTV-PyMT breast cancer mouse model; primary tumor cell isolation; in vitro tumorigenesis assays; in vivo NOD.SCID tumor growth; RhoA activation assays; siRNA knockdown of KISS1R and RhoA in MCF10A cells Cancer research Medium 21852382
2021 EGF downregulates KISS1 expression and secretion in trophoblast cells via EGFR-mediated PI3K/AKT signaling; this requires downregulation of ID3 transcription factor; KISS1 knockdown mimics EGF-induced trophoblast invasion, establishing KISS1 as a downstream effector of EGF/ID3 signaling controlling trophoblast invasiveness. RNA-seq of EGF-treated HTR-8/SVneo trophoblast cells; pathway inhibitor studies (PI3K/AKT); ID3 siRNA knockdown; KISS1 overexpression/knockdown; Transwell invasion assays Cell communication and signaling Medium 34620174
2022 Dicer ablation specifically in Kiss1 neurons causes late-onset hypogonadotropic hypogonadism; Dicer/miRNA loss predominantly reduces arcuate nucleus Kiss1 expression associated with enhanced expression of Kiss1 repressors Mkrn3, Cbx7, and Eap1, identifying a miRNA-mediated inhibitory program controlling Kiss1 expression. Kiss1-Cre conditional Dicer knockout mice; in situ hybridization for Kiss1 and repressor mRNAs; kisspeptin immunostaining; hormonal profiling; reproductive phenotyping Nature communications Medium 35945211
2013 GABAB receptor signaling normally inhibits Kiss1 expression in extrahypothalamic regions; loss of GABAB1 receptor dramatically upregulates Kiss1 in the BNST, MeA, and lateral septum in adult but not prepubertal mice, with the effect initiated during/after puberty. GABAB1 receptor knockout mice; in situ hybridization and real-time PCR for Kiss1 in multiple brain regions; sex steroid level measurements; prepubertal vs. adult comparison Endocrinology Medium 24424047
2017 Psychosocial stress rapidly suppresses pulsatile LH secretion by reducing arcuate Kiss1 neuronal activation (c-Fos induction) within 45-180 minutes, while simultaneously increasing Rfrp neuronal activation and Rfrp mRNA expression, establishing Kiss1 neuronal suppression as a mechanism linking stress to reproductive neuroendocrine inhibition. OVX mice with 5-minute interval tail-tip blood sampling for LH pulses during restraint stress; brain collection for c-Fos/Kiss1 and c-Fos/Rfrp double-label in situ hybridization; qPCR for gene expression Endocrinology Medium 28973125
2019 Insulin-induced hypoglycemia suppresses pulsatile LH secretion via suppression of arcuate Kiss1 neuronal activation (c-Fos); exogenous kisspeptin challenge restores LH secretion during hypoglycemia, placing the site of impairment upstream of GnRH neurons at the Kiss1 neuron level. OVX mouse model with serial 5-min blood sampling for pulsatile LH; insulin-induced hypoglycemia; kisspeptin challenge; c-Fos/Kiss1 co-immunofluorescence in arcuate nucleus Journal of neuroendocrinology Medium 31758872

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 1121 11385580
2012 Inactivating KISS1 mutation and hypogonadotropic hypogonadism. The New England journal of medicine 346 22335740
2010 Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 272 21093546
2010 Mutations of the KISS1 gene in disorders of puberty. The Journal of clinical endocrinology and metabolism 252 20237166
2007 Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. Journal of the National Cancer Institute 142 17312308
2003 Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases. Oncogene 134 12879005
2011 Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 132 21363930
2013 Leptin signaling in Kiss1 neurons arises after pubertal development. PloS one 117 23505551
2011 Molecular properties of Kiss1 neurons in the arcuate nucleus of the mouse. Endocrinology 115 21933870
2005 KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clinical & experimental metastasis 113 16283480
2005 KiSS-1 expression and metastin-like immunoreactivity in the rat brain. The Journal of comparative neurology 109 15593369
2012 Sex steroids and the control of the Kiss1 system: developmental roles and major regulatory actions. Journal of neuroendocrinology 108 21951227
2015 Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. Journal of neuroendocrinology 107 25582792
2010 Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biology of reproduction 102 20574054
2018 SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nature communications 98 30305620
2006 KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 96 16940711
2009 Kisspeptin-10, a KISS1-derived decapeptide, inhibits tumor angiogenesis by suppressing Sp1-mediated VEGF expression and FAK/Rho GTPase activation. Cancer research 95 19671799
2009 Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig. Biology of reproduction 91 19828777
2008 From KISS1 to kisspeptins: An historical perspective and suggested nomenclature. Peptides 91 18644415
2003 KISS1 metastasis suppression and emergent pathways. Clinical & experimental metastasis 91 12650602
2010 BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 87 20926580
2008 Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects. Peptides 86 18789989
2010 Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats. The Journal of physiology 80 20083512
2013 Shift in Kiss1 cell activity requires estrogen receptor α. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 23407940
2008 Alterations in hypothalamic KiSS-1 system in experimental diabetes: early changes and functional consequences. Endocrinology 76 18845637
2017 Acute Psychosocial Stress Inhibits LH Pulsatility and Kiss1 Neuronal Activation in Female Mice. Endocrinology 75 28973125
2014 Estradiol modulates Kiss1 neuronal response to ghrelin. American journal of physiology. Endocrinology and metabolism 75 24473434
2016 Visualisation of Kiss1 Neurone Distribution Using a Kiss1-CRE Transgenic Mouse. Journal of neuroendocrinology 74 27663274
2015 Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 25855171
2006 The KISS1 metastasis suppressor: mechanistic insights and clinical utility. Frontiers in bioscience : a journal and virtual library 74 16146758
2013 Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis. Cancer research 71 24351292
2009 Differential ovarian expression of KiSS-1 and GPR-54 during the estrous cycle and photoperiod induced recrudescence in Siberian hamsters (Phodopus sungorus). Molecular reproduction and development 67 18937338
2007 KiSS-1 system and reproduction: comparative aspects and roles in the control of female gonadotropic axis in mammals. General and comparative endocrinology 63 17324425
2011 Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma. Carcinogenesis 59 21771727
2009 KiSS1 suppresses TNFalpha-induced breast cancer cell invasion via an inhibition of RhoA-mediated NF-kappaB activation. Journal of cellular biochemistry 59 19533666
2008 Sexual differentiation and the Kiss1 system: hormonal and developmental considerations. Peptides 59 18644414
2018 The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis. Frontiers in endocrinology 58 29755406
2011 Transcriptional regulation of the human KiSS1 gene. Molecular and cellular endocrinology 57 21672609
2013 Redundancy in Kiss1 expression safeguards reproduction in the mouse. Endocrinology 55 23736293
2011 Functional interrelationship between the WASF3 and KISS1 metastasis-associated genes in breast cancer cells. International journal of cancer 53 21544801
2011 GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1. The Journal of clinical endocrinology and metabolism 51 21880801
2015 Insulin and Leptin Signaling Interact in the Mouse Kiss1 Neuron during the Peripubertal Period. PloS one 49 25946091
2010 Gonadal and nongonadal regulation of sex differences in hypothalamic Kiss1 neurones. Journal of neuroendocrinology 46 20492362
2013 Impaired GABAB receptor signaling dramatically up-regulates Kiss1 expression selectively in nonhypothalamic brain regions of adult but not prepubertal mice. Endocrinology 45 24424047
2011 Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis. Cancer research 43 21852382
2006 GPR54 and KiSS-1: role in the regulation of puberty and reproduction. Reviews in endocrine & metabolic disorders 42 17206526
2005 KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty. Endocrine 42 16034182
2018 KISS1/KISS1R in Cancer: Friend or Foe? Frontiers in endocrinology 37 30123188
2013 The Kiss1 system and polycystic ovary syndrome: lessons from physiology and putative pathophysiologic implications. Fertility and sterility 37 23809625
2011 LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty. BMC research notes 34 21939553
2014 Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer. BMC cancer 33 25260785
2011 Elevated expression of KiSS-1 in placenta of preeclampsia and its effect on trophoblast. Reproductive biology 33 21804632
2008 Changes of placental Kiss-1 mRNA expression and maternal/cord kisspeptin levels at preterm delivery. Reproductive sciences (Thousand Oaks, Calif.) 33 19017815
2012 Clinical and biological significance of KISS1 expression in prostate cancer. The American journal of pathology 32 22226740
2021 EGF stimulates human trophoblast cell invasion by downregulating ID3-mediated KISS1 expression. Cell communication and signaling : CCS 29 34620174
2020 KISS1 in metastatic cancer research and treatment: potential and paradoxes. Cancer metastasis reviews 29 32152912
2013 Lack of functional GABAB receptors alters Kiss1 , Gnrh1 and Gad1 mRNA expression in the medial basal hypothalamus at postnatal day 4. Neuroendocrinology 29 24080944
2013 Hypothalamic Expression of KiSS1 and RFamide-related Peptide-3 mRNAs during The Estrous Cycle of Rats. International journal of fertility & sterility 27 24520455
2010 Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10. European journal of endocrinology 27 21169415
2017 Effect of androgen on Kiss1 expression and luteinizing hormone release in female rats. The Journal of endocrinology 26 28377404
2022 Inhibiting Kiss1 Neurons With Kappa Opioid Receptor Agonists to Treat Polycystic Ovary Syndrome and Vasomotor Symptoms. The Journal of clinical endocrinology and metabolism 25 34387319
2019 Long noncoding RNA TC0101441 induces epithelial-mesenchymal transition in epithelial ovarian cancer metastasis by downregulating KiSS1. International journal of cancer 25 31577838
2018 ESR2 Is Essential for Gonadotropin-Induced Kiss1 Expression in Granulosa Cells. Endocrinology 25 30277501
2017 Molecular cloning and characterization of kiss1 in Brandt's voles (Lasiopodomys brandtii). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 25 28427900
2017 GLP-1 increases Kiss-1 mRNA expression in kisspeptin-expressing neuronal cells. Biology of reproduction 25 29044434
2019 KISS1 in breast cancer progression and autophagy. Cancer metastasis reviews 24 31705228
2016 The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease. PloS one 23 27158817
2016 Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function. Molecular and cellular endocrinology 23 27477782
2013 Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 23 23510953
2013 Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. Genetics & epigenetics 23 25512707
2017 KiSS1 gene as a novel mediator of TGFβ-mediated cell invasion in triple negative breast cancer. Cellular signalling 22 28988968
2023 Liraglutide ameliorates diabetic-induced testicular dysfunction in male rats: role of GLP-1/Kiss1/GnRH and TGF-β/Smad signaling pathways. Frontiers in pharmacology 21 37497106
2017 Melatonin-induced KiSS1 expression inhibits triple-negative breast cancer cell invasiveness. Oncology letters 21 28781689
2015 Differential activation of kiss receptors by Kiss1 and Kiss2 peptides in the sea bass. Reproduction (Cambridge, England) 21 26047834
2014 KISS1 methylation and expression as predictors of disease progression in colorectal cancer patients. World journal of gastroenterology 21 25110434
2019 KiSS1 in regulation of metastasis and response to antitumor drugs. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 20 30776659
2013 Association analysis between variants in KISS1 gene and litter size in goats. BMC genetics 20 23915023
2008 Expression of the metastasis suppressor gene KISS1 in uveal melanoma. Eye (London, England) 20 18219339
2005 [Expression and clinical significance of KISS-1 and GPR54 mRNA in endometrial carcinoma]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 20 15949424
2017 KISS1 tumor suppressor restricts angiogenesis of breast cancer brain metastases and sensitizes them to oncolytic virotherapy in vitro. Cancer letters 19 29269086
2015 The role of KISS1/KISS1R system in tumor growth and invasion of differentiated thyroid cancer. Anticancer research 19 25667462
2015 Honokiol suppresses metastasis of renal cell carcinoma by targeting KISS1/KISS1R signaling. International journal of oncology 19 25846316
2014 Furin is the major proprotein convertase required for KISS1-to-Kisspeptin processing. PloS one 19 24454770
2013 KiSS1 inhibits growth and invasion of osteosarcoma cells through inhibition of the MAPK pathway. European journal of histochemistry : EJH 19 24441183
2019 Ad libitum feeding triggers puberty onset associated with increases in arcuate Kiss1 and Pdyn expression in growth-retarded rats. The Journal of reproduction and development 18 31155522
2014 Kiss1 mutant placentas show normal structure and function in the mouse. Placenta 18 25468546
2012 KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis. In vivo (Athens, Greece) 18 22210725
2021 Association analysis of KISS1 polymorphisms and haplotypes with polycystic ovary syndrome. British journal of biomedical science 17 33308008
2020 MicroRNA 345 (miR345) regulates KISS1-E-cadherin functional interaction in breast cancer brain metastases. Cancer letters 17 32246957
2014 Mutational analysis of KISS1 and KISS1R in idiopathic central precocious puberty. Journal of pediatric endocrinology & metabolism : JPEM 17 23950571
2022 Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice. Nature communications 16 35945211
2020 KISS1/KISS1R and Breast Cancer: Metastasis Promoter. Seminars in reproductive medicine 16 31972865
2020 Peripheral interleukin-1β inhibits arcuate kiss1 cells and LH pulses in female mice. The Journal of endocrinology 16 32464599
2020 STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells. Journal of ovarian research 16 33218349
2019 Minireview: The Epigenetic Modulation of KISS1 in Reproduction and Cancer. International journal of environmental research and public health 16 31336647
2019 Insulin-induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice. Journal of neuroendocrinology 16 31758872
2021 Sex-specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2. eLife 15 34494548
2019 KISS1 Suppresses Apoptosis and Stimulates the Synthesis of E2 in Porcine Ovarian Granulosa Cells. Animals : an open access journal from MDPI 15 30759773
2019 Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women. BioMed research international 15 30993114
2016 Photoperiod modulates the reproductive axis of European sea bass through regulation of kiss1 and gnrh2 neuronal expression. General and comparative endocrinology 15 27641683