Affinage

KISS1

Metastasis-suppressor KiSS-1 · UniProt Q15726

Length
138 aa
Mass
14.7 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KISS1 encodes a secreted precursor that is proteolytically matured by the proprotein convertase furin into the carboxy-amidated kisspeptin peptides (kisspeptin-54/metastin and shorter fragments), which serve as the endogenous ligands for the G-protein-coupled receptor GPR54/KISS1R (PMID:11385580, PMID:24454770). Receptor engagement couples through Gαq to phospholipase C-β and intracellular Ca2+ mobilization, a signaling output demonstrated both in receptor-transfected cells and in native neurons (PMID:12359743, PMID:15593369). KISS1 functions in two largely separable physiological arenas. As a metastasis suppressor, kisspeptin-GPR54 signaling inhibits cancer cell chemotaxis, invasion, and metastatic colonization (PMID:11385580, PMID:16283480); the anti-migratory effect operates through PKCα inhibition and PKC-dependent PKD1 phosphorylation that lowers the EMT factor Slug and raises E-cadherin (PMID:16283480, PMID:24894166), and through a Gαq-p63RhoGEF-RhoA axis governing anchorage-independent growth (PMID:21852382), with secretion of the peptide required for full suppressive activity in vivo (PMID:20844932). As a master regulator of reproduction, hypothalamic kisspeptin is essential for gonadotropin secretion and puberty: Kiss1-null mice are infertile with hypogonadotropic hypogonadism, and inactivating human KISS1 mutations cause failure of pubertal progression, while gain-of-function variants are linked to central precocious puberty (PMID:17595229, PMID:22335740, PMID:20237166). Kiss1 neuronal output is set by a dense transcriptional and epigenetic control network — activated by TTF1, CUX1-p200, NHLH2, and estrogen receptors (ERα in AVPV/ARC neurons, ESR2 in granulosa cells via promoter EREs) and repressed by EAP1, YY1, CUX1-p110, SP1, and a SIRT1-Polycomb chromatin switch, with metabolic cues (adiponectin/AMPK, ghrelin, nutritional state) and miRNA programs tuning expression across the pubertal transition (PMID:21672609, PMID:23407940, PMID:30277501, PMID:34494548, PMID:30305620, PMID:22582096, PMID:35945211).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2001 High

    Established the molecular identity of KISS1 as the precursor of a secreted ligand and linked it to a specific orphan receptor, defining the entire signaling axis.

    Evidence Peptide isolation from placenta, GPR54 receptor binding/activation in transfected CHO cells, and in vitro/in vivo metastasis assays

    PMID:11385580

    Open questions at the time
    • Did not define downstream second-messenger coupling
    • In vivo source and processing of the endogenous peptide not addressed
  2. 2002 High

    Defined the proximal signaling output of the receptor, showing kisspeptin-GPR54 couples to Gαq-PLC-β/Ca2+ with anti-proliferative and anti-migratory consequences.

    Evidence Mouse ortholog identification, PLC-β activation, and proliferation/migration assays in receptor-expressing cells

    PMID:12359743

    Open questions at the time
    • Effectors downstream of Ca2+ not yet identified
    • Tissue context of signaling not addressed
  3. 2005 Medium

    Confirmed direct peptide bioactivity on native central neurons, extending signaling beyond engineered cell lines.

    Evidence Metastin-induced Ca2+ imaging in GPR54-expressing rat hippocampal neurons with peptide preabsorption controls

    PMID:15593369

    Open questions at the time
    • Physiological role in hippocampus unresolved
    • No link to behavioral or endocrine output
  4. 2005 Medium

    Identified PKCα inhibition as the mechanistic basis of kisspeptin's anti-migratory effect in cancer cells.

    Evidence KISS1 overexpression in ovarian cancer cells, migration/xenograft assays, PKC activator rescue, and PKCα shRNA knockdown

    PMID:16283480

    Open questions at the time
    • Connection to receptor engagement not directly tested
    • Single cell-line context
  5. 2007 High

    Resolved whether KISS1 is required as the in vivo ligand for reproductive function, separating ligand loss from receptor loss.

    Evidence Targeted Kiss1 and Gpr54 deletions with hormone phenotyping and kisspeptin challenge in KO mice

    PMID:17595229

    Open questions at the time
    • Did not address upstream transcriptional control of Kiss1
    • Neuronal circuit mechanism not dissected
  6. 2010 High

    Established that KISS1 dosage is physiologically tuned in humans, with loss-of-function causing hypogonadotropic hypogonadism and gain-of-function (stabilized peptide) linked to precocious puberty.

    Evidence Family sequencing of consanguineous IHH kindred and CPP patients, with serum stability and IP-accumulation assays of mutant kisspeptin-54

    PMID:20237166 PMID:22335740

    Open questions at the time
    • Mechanism of stabilized-peptide variants is correlative
    • Penetrance and modifier effects not resolved
  7. 2010 Medium

    Showed that secretion of the KISS1 product is mechanistically required for its metastasis-suppressive function.

    Evidence Orthotopic pancreatic xenograft comparing full-length vs. secretion-signal-deleted KISS1 with bioluminescence imaging

    PMID:20844932

    Open questions at the time
    • Residual activity of the non-secreted construct unexplained
    • Autocrine vs. paracrine action not separated
  8. 2011 Medium

    Extended the cancer signaling map by placing a Gαq-p63RhoGEF-RhoA pathway downstream of KISS1R controlling anchorage-independent growth.

    Evidence Kiss1r heterozygous MMTV-PyMT model, in vitro tumorigenic assays, and siRNA knockdown of KISS1R/RhoA with RhoA activation assays

    PMID:21852382

    Open questions at the time
    • Context-dependence (pro- vs. anti-tumor) not reconciled
    • Single tumor model
  9. 2011 Medium

    Began defining the KISS1 transcriptional control network, mapping the promoter and identifying both activators and repressors recruited in vivo.

    Evidence RACE-PCR TSS mapping, promoter-reporter assays, and ChIP of TTF1, CUX1, EAP1, and YY1 occupancy

    PMID:21672609

    Open questions at the time
    • Functional in vivo requirement of each factor not tested
    • Combinatorial logic unresolved
  10. 2011 Medium

    Linked KISS1 silencing to chemoresistance via a GSTπ-dependent mechanism in head and neck cancer.

    Evidence PCR arrays, KISS1 knockdown/reconstitution, GSTπ analysis, migration assays, and orthotopic survival model

    PMID:21383688

    Open questions at the time
    • Direct molecular link between KISS1 and GSTπ regulation not defined
    • Single cancer type
  11. 2012 Medium

    Connected metabolic state to Kiss1 transcription, showing adiponectin/AMPK signaling represses Kiss1 by limiting SP1 nuclear translocation.

    Evidence GT1-7 neuron treatments, promoter-luciferase, AMPKα1 siRNA, SP1 immunofluorescence, and in vivo rat hypothalamic immunostaining

    PMID:22582096

    Open questions at the time
    • Integration with other metabolic signals unresolved
    • Direct SP1 binding site not mapped
  12. 2013 High

    Demonstrated that estradiol shapes the intrinsic electrical properties of Kiss1 neurons through cell-autonomous ERα.

    Evidence Patch-clamp of Kiss1-GFP neurons plus selective ERα knockout from Kiss1 neurons in OVX/estradiol-treated mice

    PMID:23407940

    Open questions at the time
    • Downstream channel/effector targets of ERα not identified
    • AVPV vs. ARC divergence not fully resolved
  13. 2014 High

    Established furin as the proprotein convertase that processes the KISS1 precursor into bioactive kisspeptin.

    Evidence Convertase inhibitor treatment, expression profiling of six convertases, and furin/PCSK5/PCSK7 shRNA with western readout

    PMID:24454770

    Open questions at the time
    • Cleavage site stoichiometry and tissue specificity not detailed
    • Generation of shorter kisspeptin fragments not mapped
  14. 2014 Medium

    Defined a PKC-PKD1-Slug/E-cadherin axis through which kisspeptin-GPR54 suppresses breast cancer EMT and invasion.

    Evidence Kisspeptin stimulation across breast lines, migration/invasion/3D assays, GPR54 and PKD1 siRNA, and EMT-marker westerns

    PMID:24894166

    Open questions at the time
    • Relationship to the RhoA pathway not reconciled
    • In vivo validation absent
  15. 2014 Medium

    Showed estradiol gates the metabolic responsiveness of ARC Kiss1 neurons to ghrelin via GHSR upregulation.

    Evidence GHSR/ERα co-expression mapping and patch-clamp of ARC Kiss1 neurons in estradiol- vs. oil-treated OVX mice

    PMID:24473434

    Open questions at the time
    • Behavioral/endocrine consequence not measured
    • Mechanism of GHSR transcriptional induction unresolved
  16. 2014 Medium

    Extended kisspeptin Ca2+ signaling to human ovarian granulosa cells and revealed cross-talk with neurokinin B/tachykinin signaling.

    Evidence KISS1/KISS1R expression analysis and intracellular Ca2+ measurement with NKB co-stimulation and tachykinin antagonists in primary MGCs

    PMID:25316443

    Open questions at the time
    • Physiological role in folliculogenesis not established
    • Mechanism of NKB suppression undefined
  17. 2015 Medium

    Revealed a developmental lineage link between nutrient-sensing POMC progenitors and reproductive Kiss1 neurons.

    Evidence Ribotag and Pomc-Cre/Kiss1-reporter lineage tracing in mice

    PMID:25855171

    Open questions at the time
    • Functional consequence of shared lineage not tested
    • Fraction of Kiss1 neurons of POMC origin not quantified
  18. 2017 Medium

    Placed KISS1 within TGFβ/Smad2 signaling as a required mediator of invasion in triple-negative breast cancer, contrasting with its suppressive role elsewhere.

    Evidence RNA-seq target identification, KISS1 shRNA, invasion assays, MMP9 zymography, ERK inhibition, and p234 antagonist blocking

    PMID:28988968

    Open questions at the time
    • Context-dependent pro- vs. anti-invasive switch not mechanistically reconciled
    • In vivo relevance not tested
  19. 2018 High

    Identified a SIRT1-Polycomb epigenetic switch coupling nutritional state to the timing of Kiss1 derepression at puberty.

    Evidence ChIP at Kiss1 promoter, SIRT1 transgenesis, virogenetic ARC overexpression, pharmacology, and puberty-timing assays

    PMID:30305620

    Open questions at the time
    • Identity of the trigger evicting SIRT1 not defined
    • Sex-specific differences not detailed
  20. 2018 High

    Defined ESR2-driven, ERE-dependent activation of Kiss1 in ovarian granulosa cells downstream of gonadotropin/ERK and AP-1.

    Evidence ESR2 ChIP, promoter-luciferase with ERE mutation, Esr2-null rat ovary phenotyping, and phospho-ESR2 western blot

    PMID:30277501

    Open questions at the time
    • Ovarian kisspeptin function in vivo not fully defined
    • Crosstalk with hypothalamic regulation unaddressed
  21. 2021 High

    Identified NHLH2 as a direct transcriptional activator of KISS1 required cell-autonomously for normal pubertal timing.

    Evidence Drop-Seq, in situ hybridization, luciferase, ChIP on KISS1/TAC3 promoters, and conditional Nhlh2 KO from Kiss1 neurons

    PMID:34494548

    Open questions at the time
    • Sex differences in phenotype not fully resolved
    • Interaction with repressive network not mapped
  22. 2021 Medium

    Showed EGFR-PI3K/AKT signaling suppresses KISS1 via ID3 in trophoblasts to promote invasion, linking KISS1 to placental biology.

    Evidence RNA-seq, PI3K/AKT inhibition, ID3 and KISS1 siRNA, transwell invasion, and patient serum measurements in preeclampsia

    PMID:34620174

    Open questions at the time
    • Direct ID3 binding to KISS1 promoter not shown
    • Causal role in preeclampsia not established
  23. 2022 High

    Revealed a miRNA (Dicer)-dependent program that restrains Kiss1 repressors during the pubertal transition.

    Evidence Conditional Dicer KO in Kiss1-Cre mice with neuron counting, repressor qPCR (Mkrn3/Cbx7/Eap1), and puberty/hormone assays

    PMID:35945211

    Open questions at the time
    • Specific miRNAs responsible not identified
    • Female-predominant phenotype mechanism unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same kisspeptin-GPR54-Gαq axis produces opposite cellular outcomes (metastasis suppression vs. TGFβ-driven invasion) across tissue contexts remains unresolved.
  • No unifying model reconciling pro- and anti-invasive roles
  • No structural model of receptor-effector selectivity
  • Determinants of context-specific downstream effector choice (PKCα vs. RhoA vs. ERK) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
FURINGPR54KISS1R

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 KISS1 encodes a 54-amino-acid carboxy-terminally amidated peptide (metastin/kisspeptin-54) that is the endogenous ligand of the orphan G-protein-coupled receptor hOT7T175 (GPR54/KISS1R); binding of metastin to GPR54-transfected CHO cells inhibits chemotaxis and invasion in vitro, and attenuates pulmonary metastasis of GPR54-transfected B16-BL6 melanoma cells in vivo. Peptide isolation from human placenta, receptor binding/activation assays in GPR54-transfected CHO cells, in vitro chemotaxis/invasion assays, in vivo mouse melanoma metastasis model Nature High 11385580
2002 Activation of the mouse KiSS1 receptor by kisspeptin peptide couples to Gαq-mediated phospholipase C-β (PLC-β) and downstream Ca2+ signaling, and inhibits cell proliferation and cell migration in transfected cells. Identification of mouse KiSS1/receptor homologs, PLC-β activation assays, cell proliferation and migration assays in receptor-expressing cell lines Cancer research High 12359743
2005 KISS1 overexpression in ovarian cancer cells inhibits cell migration induced by serum or lysophosphatidic acid (LPA) and suppresses metastatic colonization in a mouse xenograft model; the anti-migratory effect is reversed ~80% by PKC activation, and shRNA knockdown of PKCα restores KISS1-mediated inhibition of migration, indicating PKCα inhibition as a key mechanism. KISS1 overexpression in SKOV3 cells, cell migration assays, soft-agar colony assays, xenograft mouse metastasis model, PKC activator rescue experiments, PKCα shRNA knockdown Clinical & experimental metastasis Medium 16283480
2007 Kiss1 knockout mice are infertile with hypogonadotropic hypogonadism (reduced FSH, small testes/ovaries), confirming that kisspeptin is required as the ligand for GPR54 to gate sexual maturation; Kiss1 KO mice, unlike Gpr54 KO mice, respond to exogenous kisspeptin with gonadotropin release, confirming the receptor remains functional. Targeted gene deletion of Kiss1 or Gpr54 on matched genetic background, gonadal morphometry, hormone measurements, kisspeptin challenge in KO mice Endocrinology High 17595229
2010 An inactivating homozygous missense mutation in KISS1 in humans causes failure of pubertal progression (hypogonadotropic hypogonadism), establishing that functional kisspeptin is required for puberty and reproduction in humans. Whole-gene sequencing in a large consanguineous human family; identification of inactivating KISS1 mutation; clinical phenotyping The New England journal of medicine High 22335740
2010 Two KISS1 missense mutations (p.P74S and p.H90D) found in children with idiopathic central precocious puberty (CPP); the P74S variant shows increased resistance to serum degradation compared to wild-type kisspeptin-54, suggesting prolonged biological activity as a gain-of-function mechanism. Gene sequencing in CPP/IHH patients, in vitro IP accumulation assay with wild-type and mutant kp54, serum stability assay The Journal of clinical endocrinology and metabolism Medium 20237166
2014 Furin is the major proprotein convertase responsible for processing the KISS1 precursor protein into kisspeptin peptides; shRNA knockdown of furin (but not PCSK5 or PCSK7) blocks KISS1 processing in cell lines, and broad proprotein convertase inhibitors (Dec-RVKR-CMK and α1-PDX) completely inhibit processing. Proprotein convertase inhibitor treatment of KISS1-overexpressing cell lines, systematic mRNA expression analysis of six convertases, shRNA knockdown of furin/PCSK5/PCSK7 with western blot readout of KISS1 processing PloS one High 24454770
2010 Secretion of KISS1 is required for its full metastasis-suppressive activity; overexpression of a KISS1 construct lacking the secretion signal sequence (KFMΔSS) reduced but did not abolish liver/lung metastases in an orthotopic pancreatic cancer mouse model, whereas full-length KISS1 virtually eliminated lung metastases. Orthotopic SCID mouse xenograft with luciferase-labeled S2VP10 cells expressing full-length KISS1, secretion-signal-deleted KISS1 (KFMΔSS), or control; bioluminescence imaging; IHC Clinical & experimental metastasis Medium 20844932
2014 KiSS1/GPR54 signaling inhibits breast cancer cell migration and epithelial-mesenchymal transition (EMT) via PKC-dependent phosphorylation of protein kinase D1 (PKD1), which in turn decreases the EMT transcription factor Slug and increases E-cadherin expression; GPR54 or PKD1 knockdown increases migration and invasion. Kisspeptin stimulation of multiple breast cancer cell lines, migration/invasion assays, 3D matrigel colony assay, siRNA knockdown of GPR54 and PKD1, western blot of pPKD1/Slug/E-cadherin Current molecular medicine Medium 24894166
2011 Loss of KISS1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells is mechanistically linked to increased glutathione S-transferase-π (GSTπ) expression and function; genetic reconstitution of KISS1 in resistant cells restores cisplatin sensitivity and abrogates cell migration, and improves survival in an orthotopic mouse model. PCR arrays identifying KISS1 suppression in CDDP-resistant cell lines, KISS1 knockdown/overexpression, GSTπ expression analysis, in vitro migration assays, orthotopic mouse model, survival analysis Oncogene Medium 21383688
2011 KISS1R (GPR54) activation by kisspeptin-10 in mammary tumor cells signals through Gαq-p63RhoGEF to activate RhoA; RhoA-dependent anchorage-independent growth correlates with dose-dependent KISS1R-mediated RhoA regulation, and siRNA knockdown of KISS1R or RhoA inactivation reduces Ras-induced anchorage-independent growth in MCF10A cells. Kiss1r heterozygous MMTV-PyMT mouse model, primary tumor cell isolation, in vitro tumorigenic assays, in vivo growth in NOD.SCID mice, siRNA knockdown of KISS1R/RhoA, RhoA activation assays Cancer research Medium 21852382
2011 The transcription factors TTF1 and CUX1-p200 activate the human KISS1 promoter, while EAP1, YY1, and CUX1-p110 repress it; all four factors are recruited in vivo to the KISS1 promoter (ChIP) and are expressed in kisspeptin neurons; a single transcription start site was mapped 153–156 bp upstream of the ATG. RACE-PCR to map TSS, promoter-reporter assays in 293 MSR and GT1-7 cells, ChIP of endogenous promoter occupancy Molecular and cellular endocrinology Medium 21672609
2012 Adiponectin reduces Kiss1 gene transcription in hypothalamic GT1-7 neurons via AMPK activation; AMPK activation decreases nuclear translocation of specificity protein-1 (SP1), which reduces KISS1 promoter activity and mRNA levels; AMPK inhibition has the opposite effect, confirmed in vivo in rat hypothalamus. GT1-7 cell treatment with globular adiponectin/AICAR/Compound C, KISS1 mRNA and promoter-luciferase assays, AMPKα1 siRNA, SP1 nuclear translocation immunofluorescence, in vivo rat hypothalamic kisspeptin immunostaining The Journal of endocrinology Medium 22582096
2013 Kiss1 neurons in the AVPV/PeN exhibit estradiol-dependent shifts in firing pattern (resting membrane potential, cell capacitance, and spontaneous IPSC amplitude); these changes require estrogen receptor α (ERα) in Kiss1 neurons, as mice with selective ERα deletion from Kiss1 neurons show cellular activity similar to ovariectomized females. Patch-clamp electrophysiology of Kiss1-GFP neurons in brain slices, selective ERα knockout from Kiss1 neurons (Cre-lox), estradiol treatment of OVX mice The Journal of neuroscience High 23407940
2014 Estradiol increases GHSR mRNA expression and colocalization of GHSR with ERα selectively in ARC Kiss1 neurons; ghrelin acutely depolarizes a higher proportion of ARC Kiss1 neurons in estradiol-treated OVX mice (75%) versus OVX controls (25%), demonstrating that estradiol modulates the responsiveness of kisspeptin neurons to ghrelin. GHSR/ERα co-expression by in situ hybridization/immunofluorescence, patch-clamp electrophysiology of ARC Kiss1 neurons in estradiol-treated vs. oil-treated OVX mice American journal of physiology. Endocrinology and metabolism Medium 24473434
2018 SIRT1, a fuel-sensing deacetylase, epigenetically represses Kiss1 expression by interacting with the Polycomb silencing complex to decrease Kiss1 promoter activity; SIRT1 is expressed in hypothalamic Kiss1 neurons; as puberty approaches, SIRT1 is evicted from the Kiss1 promoter permitting a repressive-to-permissive chromatin switch; overnutrition accelerates these changes and advances puberty, while undernutrition raises SIRT1 and delays puberty. ChIP for SIRT1 and Polycomb components at Kiss1 promoter, SIRT1 transgenic mice, virogenetic SIRT1 overexpression in ARC, pharmacological SIRT1 activation, Kiss1 expression and puberty timing assays Nature communications High 30305620
2018 Gonadotropin-stimulated KISS1 expression in ovarian granulosa cells requires estrogen receptor β (ESR2); ESR2 binds to estrogen response elements (EREs) in the Kiss1 promoter and enhancers; gonadotropin-induced MAPK ERK2 phosphorylates ESR2, and AP-1 factors FOSL2/JUNB synergistically activate the Kiss1 promoter; mutation of the ERE within the Kiss1 promoter blocks ESR2-driven activity. ESR2 ChIP on Kiss1 promoter/enhancers in granulosa cells, Kiss1 promoter-luciferase assays with ESR2 overexpression and ERE mutation, Esr2-null rat ovary phenotyping, phospho-ESR2 western blot Endocrinology High 30277501
2017 KISS1 is a downstream target of canonical TGFβ/Smad2 signaling in triple-negative breast cancer (TNBC) cells; KISS1 expression is required for TGFβ-induced invasion and MMP9 induction; kisspeptin-10 (KP-10) independently stimulates TNBC cell invasion through MAPK/ERK activation; a KISS1 small peptide antagonist (p234) blocks TGFβ-mediated invasion. RNA-seq identification of KISS1 as TGFβ target, KISS1 knockdown with shRNA, invasion assays, MMP9 activity by zymography, ERK inhibitor experiments, KP-10 treatment, p234 antagonist blocking Cellular signalling Medium 28988968
2021 EGF downregulates KISS1 expression in human trophoblast cells via EGFR-mediated PI3K/AKT signaling; this requires downregulation of the transcription factor ID3, which is needed for KISS1 expression; functionally, EGF-mediated KISS1 suppression promotes trophoblast invasion. RNA-seq in EGF-treated HTR-8/SVneo cells identifying KISS1 as a target, PI3K/AKT inhibitor experiments, ID3 siRNA knockdown, KISS1 siRNA, transwell invasion assays, serum EGF and KISS1 measurements in preeclampsia patients Cell communication and signaling : CCS Medium 34620174
2021 NHLH2 (Nescient Helix-Loop-Helix 2) transcription factor is enriched in Kiss1 neurons and directly binds to and activates the KISS1 and TAC3 promoters (confirmed by ChIP); conditional ablation of Nhlh2 from Kiss1 neurons in male mice delays puberty and decreases arcuate Kiss1 expression, with impaired LH response to metabolic challenge. Drop-Seq of arcuate nucleus, in situ hybridization, in vitro luciferase assays, ChIP for NHLH2 on KISS1/TAC3 promoters, conditional Nhlh2 knockout from Kiss1 neurons (Kiss1Cre:Nhlh2fl/fl), puberty timing and LH assays eLife High 34494548
2022 Congenital ablation of Dicer in Kiss1 neurons causes late-onset hypogonadotropic hypogonadism predominantly in females; failure to complete puberty is associated with reduced arcuate-nucleus Kiss1 levels linked to enhanced expression of Kiss1 repressors Mkrn3, Cbx7, and Eap1, revealing a miRNA-mediated inhibitory program that controls Kiss1 expression during pubertal transition. Conditional Dicer knockout in Kiss1-Cre mice, Kiss1 neuron counting, Kiss1/kisspeptin expression analysis, qPCR of repressors Mkrn3/Cbx7/Eap1, LH/FSH measurements, puberty timing assays Nature communications High 35945211
1998 The KISS1 gene maps to chromosome 1q32 and consists of four exons; the first two exons are non-translated, exon 3 contains the translational start site, and exon 4 contains the bulk of the coding sequence and the polyadenylation signal. Genomic sequencing, radiation hybrid mapping, FISH Genomics Medium 9806840
2015 Kiss1 neurons in the hypothalamus derive developmentally from POMC-expressing progenitors, establishing a developmental lineage link between nutrient-sensing (POMC/AgRP) and reproductive (Kiss1) neuropeptide-synthesizing neuronal populations. Embryonic and adult ribosome-tagging strategy in mice (Ribotag), lineage tracing with Pomc-Cre and Kiss1-reporter crosses The Journal of neuroscience Medium 25855171
2020 ARC Kiss1 neurons project rostrally to periventricular and preoptic areas and to the lateral hypothalamus, as visualized by CLARITY 3D processing of whole brains from Kiss1-CRE:tdTomato reporter mice; ~80–90% of ARC tdTomato neurons co-label with kisspeptin, confirming high fidelity of the reporter. Kiss1-CRE transgenic mice crossed with tdTomato reporter, CLARITY whole-brain 3D imaging, co-immunolabeling for kisspeptin Journal of neuroendocrinology Medium 27663274
2014 Kisspeptin activates intracellular Ca2+ ([Ca2+]i) signaling in human ovarian mural granulosa cells (MGCs) via KISS1R; NKB co-stimulation partially suppresses this kisspeptin-induced Ca2+ response, with the inhibitory effect requiring a cocktail of NK1/NK2/NK3 receptor antagonists for reversal. RT-PCR and western blot for KISS1/KISS1R in MGCs/cumulus cells, intracellular Ca2+ measurement after kisspeptin and NKB treatment, tachykinin receptor antagonist experiments Human reproduction (Oxford, England) Medium 25316443
2005 Metastin (kisspeptin) increases intracellular Ca2+ ([Ca2+]i) in cultured rat hippocampal neurons that express GPR54, demonstrating direct biological activity of the KISS1-derived peptide in central neurons. GPR54 expression confirmed in hippocampal neurons, metastin-induced Ca2+ imaging, preabsorption controls with metastin peptide fragment The Journal of comparative neurology Medium 15593369

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 1125 11385580
2007 Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 413 17595229
2012 Inactivating KISS1 mutation and hypogonadotropic hypogonadism. The New England journal of medicine 350 22335740
2010 Mutations of the KISS1 gene in disorders of puberty. The Journal of clinical endocrinology and metabolism 252 20237166
2002 Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer research 163 12359743
1998 Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics 151 9806840
2011 Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 133 21363930
2005 KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clinical & experimental metastasis 113 16283480
2012 Sex steroids and the control of the Kiss1 system: developmental roles and major regulatory actions. Journal of neuroendocrinology 109 21951227
2005 KiSS-1 expression and metastin-like immunoreactivity in the rat brain. The Journal of comparative neurology 109 15593369
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 99 30305620
2006 KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 96 16940711
2009 Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig. Biology of reproduction 91 19828777
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 88 20926580
2008 Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects. Peptides 86 18789989
2013 Shift in Kiss1 cell activity requires estrogen receptor α. The Journal of neuroscience : the official journal of the Society for Neuroscience 79 23407940
2016 Visualisation of Kiss1 Neurone Distribution Using a Kiss1-CRE Transgenic Mouse. Journal of neuroendocrinology 76 27663274
2014 Estradiol modulates Kiss1 neuronal response to ghrelin. American journal of physiology. Endocrinology and metabolism 75 24473434
2006 The KISS1 metastasis suppressor: mechanistic insights and clinical utility. Frontiers in bioscience : a journal and virtual library 75 16146758
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
2010 The KISS1 metastasis suppressor: a good night kiss for disseminated cancer cells. European journal of cancer (Oxford, England : 1990) 66 20303258
2012 Adiponectin inhibits KISS1 gene transcription through AMPK and specificity protein-1 in the hypothalamic GT1-7 neurons. The Journal of endocrinology 64 22582096
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
2018 The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis. Frontiers in endocrinology 59 29755406
2008 Sexual differentiation and the Kiss1 system: hormonal and developmental considerations. Peptides 59 18644414
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 56 23736293
2010 KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model. Clinical & experimental metastasis 53 20844932
2014 Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. Human reproduction (Oxford, England) 51 25316443
2011 GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1. The Journal of clinical endocrinology and metabolism 51 21880801
2013 Sex-specific expression of estrogen receptors α and β and Kiss1 in the postnatal rat amygdala. The Journal of comparative neurology 50 22791648
2006 The role of KiSS-1 in the regulation of puberty in higher primates. European journal of endocrinology 48 17074983
2010 Gonadal and nongonadal regulation of sex differences in hypothalamic Kiss1 neurones. Journal of neuroendocrinology 46 20492362
2011 Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis. Cancer research 43 21852382
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 39 30123188
2017 G protein-coupled KISS1 receptor is overexpressed in triple negative breast cancer and promotes drug resistance. Scientific reports 38 28422142
2015 Delayed pubertal onset and prepubertal Kiss1 expression in female mice lacking central oestrogen receptor beta. Human molecular genetics 37 26464488
2013 The Kiss1 system and polycystic ovary syndrome: lessons from physiology and putative pathophysiologic implications. Fertility and sterility 37 23809625
2009 Expression of KiSS-1 gene and its role in invasion and metastasis of human hepatocellular carcinoma. Anatomical record (Hoboken, N.J. : 2007) 37 19645016
2014 Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer. BMC cancer 34 25260785
2011 Elevated expression of KiSS-1 in placenta of preeclampsia and its effect on trophoblast. Reproductive biology 33 21804632
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
2012 KiSS1 and its G-protein-coupled receptor GPR54 in cancer development and metastasis. Cancer metastasis reviews 29 22692479
2011 KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma. Oncogene 28 21383688
2013 Developmental profile and sexually dimorphic expression of kiss1 and kiss1r in the fetal mouse brain. Frontiers in endocrinology 27 24130552
2013 Hypothalamic Expression of KiSS1 and RFamide-related Peptide-3 mRNAs during The Estrous Cycle of Rats. International journal of fertility & sterility 27 24520455
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
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
2016 Immunohistochemical expression pattern of metastasis suppressors KAI1 and KISS1 in endometriosis and normal endometrium. European journal of obstetrics, gynecology, and reproductive biology 25 26918694
2019 KISS1 in breast cancer progression and autophagy. Cancer metastasis reviews 24 31705228
2016 Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function. Molecular and cellular endocrinology 24 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 24 23510953
2013 Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. Genetics & epigenetics 23 25512707
2020 Conditional kisspeptin neuron-specific Kiss1 knockout with newly generated Kiss1-floxed and Kiss1-Cre mice replicates a hypogonadal phenotype of global Kiss1 knockout mice. The Journal of reproduction and development 22 32307336
2017 KiSS1 gene as a novel mediator of TGFβ-mediated cell invasion in triple negative breast cancer. Cellular signalling 22 28988968
2017 Melatonin-induced KiSS1 expression inhibits triple-negative breast cancer cell invasiveness. Oncology letters 21 28781689
2014 KISS1 methylation and expression as predictors of disease progression in colorectal cancer patients. World journal of gastroenterology 21 25110434
2014 KISS1 gene polymorphisms in Korean girls with central precocious puberty. Journal of Korean medical science 21 25120323
2019 KiSS1 in regulation of metastasis and response to antitumor drugs. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 20 30776659
2018 Increased Expression of KISS1 and KISS1 Receptor in Human Granulosa Lutein Cells-Potential Pathogenesis of Polycystic Ovary Syndrome. Reproductive sciences (Thousand Oaks, Calif.) 20 30595091
2014 KiSS1-induced GPR54 signaling inhibits breast cancer cell migration and epithelial-mesenchymal transition via protein kinase D1. Current molecular medicine 20 24894166
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
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
2021 Association analysis of KISS1 polymorphisms and haplotypes with polycystic ovary syndrome. British journal of biomedical science 18 33308008
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
2020 MicroRNA 345 (miR345) regulates KISS1-E-cadherin functional interaction in breast cancer brain metastases. Cancer letters 17 32246957
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 Role of the tumor microenvironment in regulating the anti-metastatic effect of KISS1. Clinical & experimental metastasis 16 32088827
2020 STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells. Journal of ovarian research 16 33218349
2019 Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women. BioMed research international 16 30993114
2019 Minireview: The Epigenetic Modulation of KISS1 in Reproduction and Cancer. International journal of environmental research and public health 16 31336647
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
2016 Expression of EAP1 and CUX1 in the hypothalamus of female rats and relationship with KISS1 and GnRH. Endocrine journal 15 27250217
2020 Expression of genes for Kisspeptin (KISS1), Neurokinin B (TAC3), Prodynorphin (PDYN), and gonadotropin inhibitory hormone (RFRP) across natural puberty in ewes. Physiological reports 14 32170819
2017 The metastasis suppressor gene KISS-1 regulates osteosarcoma apoptosis and autophagy processes. Molecular medicine reports 13 28075440
2015 Polymorphisms rs12998 and rs5780218 in KiSS1 suppressor metastasis gene in Mexican patients with breast cancer. Disease markers 13 25810563
2013 KISS1 expression in colorectal cancer. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 13 24033850
2014 Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity. Journal of medicinal chemistry 12 24918545
2023 KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers? Cancer metastasis reviews 11 36720764
2020 Influence of KISS1 gene polymorphisms on the risk of polycystic ovary syndrome and its associated variables, in Saudi women. BMC endocrine disorders 11 32380991
2018 KISS1 and KISS1R expression in gastric cancer. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 11 29552764
2015 A clinicopathological analysis of KISS1 and KISS1R expression in colorectal cancer. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 11 26010933
2023 CRISPR/Cas9-editing of KISS1 to generate pigs with hypogonadotropic hypogonadism as a castration free trait. Frontiers in genetics 10 36685939
2023 Sex difference in developmental changes in visualized Kiss1 neurons in newly generated Kiss1-Cre rats. The Journal of reproduction and development 10 37518187
2022 Immunocastration with gene vaccine (KISS1) induces a cell-mediated immune response in ram testis: A transcriptome evaluation. Reproduction in domestic animals = Zuchthygiene 10 35247007
2020 Local expressions and function of Kiss1/GPR54 in goats' testes. Gene 10 32087275
2018 Kiss1 and its receptor: molecular characterization and immunolocalization in the hypothalamus and corpus luteum of the buffalo. Animal biotechnology 10 30444171
2004 Differential expression of the closely linked KISS1, REN, and FLJ10761 genes in transgenic mice. Physiological genomics 10 14709678

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