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Cyclin-dependent kinase inhibitor 1C

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CDKN1C
Identifiers
AliasesCDKN1C, BWCR, BWS, KIP2, WBS, p57, p57Kip2, cyclin-dependent kinase inhibitor 1C, cyclin dependent kinase inhibitor 1C
External IDsOMIM: 600856; MGI: 104564; HomoloGene: 133549; GeneCards: CDKN1C; OMA:CDKN1C - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1028

12577

Ensembl

ENSG00000273707
ENSG00000129757

ENSMUSG00000037664

UniProt

P49918

P49919

RefSeq (mRNA)

NM_000076
NM_001122630
NM_001122631
NM_001362474
NM_001362475

NM_001161624
NM_009876
NM_001354981

RefSeq (protein)

NP_000067
NP_001116102
NP_001116103
NP_001349403
NP_001349404

NP_001155096
NP_034006
NP_001341910

Location (UCSC)Chr 11: 2.88 – 2.89 MbChr 7: 143.01 – 143.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-dependent kinase inhibitor 1C (p57, Kip2), also known as CDKN1C, is a protein which in humans is encoded by the CDKN1C imprinted gene.[5]

Function

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Cyclin-dependent kinase inhibitor 1C is a tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations of CDKN1C are implicated in sporadic cancers and Beckwith-Wiedemann syndrome suggesting that it is a tumor suppressor candidate.[5]

CDKN1C is a tumor suppressor human gene on chromosome 11 (11p15) and belongs to the cip/kip gene family. It encodes a cell cycle inhibitor that binds to G1 cyclin-CDK complexes.[6] Thus p57KIP2 causes arrest of the cell cycle in G1 phase.

CDKN1C was found to lead to cancer cell dormancy; its gene expression is regulated through the activity of glucocorticoid receptors (GRs) through chromatin remodelling mediated by SWI/SNF.[7]

Research Methods

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Since it has been identified that mutation to this tumor suppressing gene can have dramatic effects in a newborn such as macroglossia there has been great research to determine the genetic significance. CDKN1C is prone to error during the process of gene imprinting. The process of gene imprinting is in concert with DNA methylation. This goes makes the gene become transcriptionally silent from the paternal side allowing the maternal gene to be active.[8] If this gene fails to be properly methylated, or obtains a mutation, there will be a lack of cell cycle suppression leading to the pediatric tumor growth.[9]

Research methods for this gene have involved different sequencing methods such as Sanger Sequencing. This sequencing method is a three step process that involves PCR, Gel Electrophoresis, and computer analysis to determine DNA sequences.[10] Sequencing can be helpful in identifying base pair mutations. A study done to assess the phenotypic effects that mutations to this gene will have taken genetic sequencing of a cohort of individuals known to be effected by a mutation on this gene. [11] In this study, they found 37 mutations associated with 38 different pedigrees. This went to prove that mutations to the CDKN1C on chromosome 11 would in fact have phenotypic effects on individuals. These effects are further discussed through the different clinical cases that can occur.

Clinical significance

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A mutation of this gene may lead to loss of control over the cell cycle leading to uncontrolled cellular proliferation. p57KIP2 has been associated with Beckwith-Wiedemann syndrome (BWS) which is characterized by increased risk of tumor formation in childhood.[12] Loss-of-function mutations in this gene have also been shown associated to the IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies).[13] Complete hydatidiform moles consist only of paternal DNA, and thus the cells lack p57 expression as the gene is paternally imprinted (silenced). Immunohistochemical stains for p57 can aid with the diagnosis of hydatidiform moles.[14]

Interactions

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Cyclin-dependent kinase inhibitor 1C has been shown to interact with:

References

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  1. ^ a b c ENSG00000129757 GRCh38: Ensembl release 89: ENSG00000273707, ENSG00000129757 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037664 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2)".
  6. ^ Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ (Mar 1995). "p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene". Genes & Development. 9 (6): 650–62. doi:10.1101/gad.9.6.650. PMID 7729684.
  7. ^ Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B (July 2021). "Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer". Nature Communications. 12 (1): 4360. Bibcode:2021NatCo..12.4360P. doi:10.1038/s41467-021-24537-3. PMC 8285479. PMID 34272384.
  8. ^ Amacher S. "Epigenetics Impriting" (PDF). University of California Berkeley.
  9. ^ Cedar H, Bergman Y (May 2009). "Linking DNA methylation and histone modification: patterns and paradigms". Nature Reviews. Genetics. 10 (5): 295–304. doi:10.1038/nrg2540. PMID 19308066. S2CID 5450674.
  10. ^ "Sanger Sequencing Steps & Method". Merck KGaA. Darmstadt, Germany.
  11. ^ Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, et al. (September 2015). "Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization". Human Mutation. 36 (9): 894–902. doi:10.1002/humu.22824. PMID 26077438. S2CID 37398295.
  12. ^ Hatada I, Nabetani A, Morisaki H, Xin Z, Ohishi S, Tonoki H, Niikawa N, Inoue M, Komoto Y, Okada A, Steichen E, Ohashi H, Fukushima Y, Nakayama M, Mukai T (Oct 1997). "New p57KIP2 mutations in Beckwith-Wiedemann syndrome". Human Genetics. 100 (5–6): 681–3. doi:10.1007/s004390050573. PMID 9341892. S2CID 21120202.
  13. ^ Riccio A, Cubellis MV (Jul 2012). "Gain of function in CDKN1C". Nature Genetics. 44 (7): 737–8. doi:10.1038/ng.2336. PMID 22735584. S2CID 205345787.
  14. ^ LeGallo RD, Stelow EB, Ramirez NC, Atkins KA (May 2008). "Diagnosis of hydatidiform moles using p57 immunohistochemistry and HER2 fluorescent in situ hybridization". American Journal of Clinical Pathology. 129 (5): 749–755. doi:10.1309/7XRL378C22W7APBT. PMID 18426735.
  15. ^ Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N (Dec 2003). "p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus". The Journal of Biological Chemistry. 278 (52): 52919–23. doi:10.1074/jbc.M309334200. PMID 14530263.
  16. ^ Joaquin M, Watson RJ (Nov 2003). "The cell cycle-regulated B-Myb transcription factor overcomes cyclin-dependent kinase inhibitory activity of p57(KIP2) by interacting with its cyclin-binding domain". The Journal of Biological Chemistry. 278 (45): 44255–64. doi:10.1074/jbc.M308953200. PMID 12947099.
  17. ^ Reynaud EG, Leibovitch MP, Tintignac LA, Pelpel K, Guillier M, Leibovitch SA (Jun 2000). "Stabilization of MyoD by direct binding to p57(Kip2)". The Journal of Biological Chemistry. 275 (25): 18767–76. doi:10.1074/jbc.M907412199. PMID 10764802.
  18. ^ Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y (Feb 1998). "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1392–7. Bibcode:1998PNAS...95.1392W. doi:10.1073/pnas.95.4.1392. PMC 19016. PMID 9465025.

Further reading

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