Cyclin-dependent kinase inhibitor 1C explained

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

Function

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.

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.^[2] 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.^[3]

Research Methods

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.^[4] 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.^[5]

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.^[6] 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. ^[7] 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

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.^[8] 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).^[9] 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.^[10]

Interactions

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

• LIMK1,^[11]
• MYBL2,^[12]
• MyoD,^[13] and
• PCNA.^[14]

Further reading

• Seizinger BR . Genes associated with tumor suppression and growth control in the human nervous system . Cancer and Metastasis Reviews . 10 . 4 . 281–7 . Dec 1991 . 1786629 . 10.1007/BF00554790 . 22809027 .
• Lee MH, Reynisdóttir I, Massagué J . Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution . Genes & Development . 9 . 6 . 639–49 . Mar 1995 . 7729683 . 10.1101/gad.9.6.639 . free .
• Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ . p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene . Genes & Development . 9 . 6 . 650–62 . Mar 1995 . 7729684 . 10.1101/gad.9.6.650 . free .
• Matsuoka S, Thompson JS, Edwards MC, Bartletta JM, Grundy P, Kalikin LM, Harper JW, Elledge SJ, Feinberg AP . Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15 . Proceedings of the National Academy of Sciences of the United States of America . 93 . 7 . 3026–30 . Apr 1996 . 8610162 . 39755 . 10.1073/pnas.93.7.3026 . 1996PNAS...93.3026M . free .
• Reid LH, Crider-Miller SJ, West A, Lee MH, Massagué J, Weissman BE . Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms' tumor assay . Cancer Research . 56 . 6 . 1214–8 . Mar 1996 . 8640800 .
• Tokino T, Urano T, Furuhata T, Matsushima M, Miyatsu T, Sasaki S, Nakamura Y . Characterization of the human p57KIP2 gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis . Human Genetics . 97 . 5 . 625–31 . May 1996 . 8655143 . 10.1007/BF02281873 . 1833559 .
• Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, Okada A, Ohishi S, Nabetani A, Morisaki H, Nakayama M, Niikawa N, Mukai T . An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome . Nature Genetics . 14 . 2 . 171–3 . Oct 1996 . 8841187 . 10.1038/ng1096-171 . 1765772 .
• Furuhata T, Tokino T, Urano T, Nakamura Y . Isolation of a novel GPI-anchored gene specifically regulated by p53; correlation between its expression and anti-cancer drug sensitivity . Oncogene . 13 . 9 . 1965–70 . Nov 1996 . 8934543 .
• LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E . New functional activities for the p21 family of CDK inhibitors . Genes & Development . 11 . 7 . 847–62 . Apr 1997 . 9106657 . 10.1101/gad.11.7.847 . free .
• Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y . 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 . Feb 1998 . 9465025 . 19016 . 10.1073/pnas.95.4.1392 . 1998PNAS...95.1392W . free .
• Bhuiyan ZA, Yatsuki H, Sasaguri T, Joh K, Soejima H, Zhu X, Hatada I, Morisaki H, Morisaki T, Mukai T . Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome . Human Genetics . 104 . 3 . 205–10 . Mar 1999 . 10323243 . 10.1007/s004390050937 . 25081259 .
• Lam WW, Hatada I, Ohishi S, Mukai T, Joyce JA, Cole TR, Donnai D, Reik W, Schofield PN, Maher ER . Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation . Journal of Medical Genetics . 36 . 7 . 518–23 . Jul 1999 . 10424811 . 1734395 . 10.1136/jmg.36.7.518 .
• Reynaud EG, Leibovitch MP, Tintignac LA, Pelpel K, Guillier M, Leibovitch SA . Stabilization of MyoD by direct binding to p57(Kip2) . The Journal of Biological Chemistry . 275 . 25 . 18767–76 . Jun 2000 . 10764802 . 10.1074/jbc.M907412199 . free .
• Fink JR, LeBien TW . Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors . Experimental Hematology . 29 . 4 . 490–8 . Apr 2001 . 11301189 . 10.1016/S0301-472X(01)00619-1 . free .
• Kido K, Doerks A, Lochelt M, Flügel RM . Identification and functional characterization of an intragenic DNA binding site for the spumaretroviral trans-activator in the human p57Kip2 gene . The Journal of Biological Chemistry . 277 . 14 . 12032–9 . Apr 2002 . 11815601 . 10.1074/jbc.M108747200 . free .
• Balint E, Phillips AC, Kozlov S, Stewart CL, Vousden KH . Induction of p57(KIP2) expression by p73beta . Proceedings of the National Academy of Sciences of the United States of America . 99 . 6 . 3529–34 . Mar 2002 . 11891335 . 122557 . 10.1073/pnas.062491899 . 2002PNAS...99.3529B . free .
• Ito Y, Yoshida H, Nakano K, Kobayashi K, Yokozawa T, Hirai K, Matsuzuka F, Matsuura N, Kuma K, Miyauchi A . Expression of p57/Kip2 protein in normal and neoplastic thyroid tissues . International Journal of Molecular Medicine . 9 . 4 . 373–6 . Apr 2002 . 11891530 . 10.3892/ijmm.9.4.373 .
• Kikuchi T, Toyota M, Itoh F, Suzuki H, Obata T, Yamamoto H, Kakiuchi H, Kusano M, Issa JP, Tokino T, Imai K . Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors . Oncogene . 21 . 17 . 2741–9 . Apr 2002 . 11965547 . 10.1038/sj.onc.1205376 . free .
• Li Y, Nagai H, Ohno T, Yuge M, Hatano S, Ito E, Mori N, Saito H, Kinoshita T . 13999973 . Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype . Blood . 100 . 7 . 2572–7 . Oct 2002 . 12239171 . 10.1182/blood-2001-11-0026 . free .

External links

• GeneReviews/NIH/NCBI/UW entry on Beckwith-Wiedemann Syndrome

Notes and References

1. Web site: Entrez Gene: CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2).
2. Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ . p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene . Genes & Development . 9 . 6 . 650–62 . Mar 1995 . 7729684 . 10.1101/gad.9.6.650 . free .
3. Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B. Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer. Nature Communications. 12. 1. July 2021. 4360. 10.1038/s41467-021-24537-3. 34272384. 8285479. 2021NatCo..12.4360P . free .
4. Web site: Amacher S . Epigenetics Impriting . University of California Berkeley .
5. Cedar H, Bergman Y . Linking DNA methylation and histone modification: patterns and paradigms . Nature Reviews. Genetics . 10 . 5 . 295–304 . May 2009 . 19308066 . 10.1038/nrg2540 . 5450674 .
6. Web site: Sanger Sequencing Steps & Method . Merck KGaA . Darmstadt, Germany .
7. Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, Edery P, Catala M, Odent S, Isidor B, Lyonnet S, Sigaudy S, Leheup B, Audebert-Bellanger S, Burglen L, Giuliano F, Alessandri JL, Cormier-Daire V, Laffargue F, Blesson S, Coupier I, Lespinasse J, Blanchet P, Boute O, Baumann C, Polak M, Doray B, Verloes A, Viot G, Le Bouc Y, Rossignol S . 6 . 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 . September 2015 . 26077438 . 10.1002/humu.22824 . 37398295 . free .
8. 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 . New p57KIP2 mutations in Beckwith-Wiedemann syndrome . Human Genetics . 100 . 5–6 . 681–3 . Oct 1997 . 9341892 . 10.1007/s004390050573 . 21120202 .
9. Riccio A, Cubellis MV . Gain of function in CDKN1C . Nature Genetics . 44 . 7 . 737–8 . Jul 2012 . 22735584 . 10.1038/ng.2336 . 205345787 . free .
10. LeGallo RD, Stelow EB, Ramirez NC, Atkins KA . Diagnosis of hydatidiform moles using p57 immunohistochemistry and HER2 fluorescent in situ hybridization . American Journal of Clinical Pathology . 129 . 5 . 749–755 . May 2008 . 18426735 . 10.1309/7XRL378C22W7APBT . free .
11. Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N . p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus . The Journal of Biological Chemistry . 278 . 52 . 52919–23 . Dec 2003 . 14530263 . 10.1074/jbc.M309334200 . free .
12. Joaquin M, Watson RJ . 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 . Nov 2003 . 12947099 . 10.1074/jbc.M308953200 . free .
13. Reynaud EG, Leibovitch MP, Tintignac LA, Pelpel K, Guillier M, Leibovitch SA . Stabilization of MyoD by direct binding to p57(Kip2) . The Journal of Biological Chemistry . 275 . 25 . 18767–76 . Jun 2000 . 10764802 . 10.1074/jbc.M907412199 . free .
14. Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y . 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 . Feb 1998 . 9465025 . 19016 . 10.1073/pnas.95.4.1392. 1998PNAS...95.1392W . free .