Cyclin-dependent kinase inhibitor 1C

Cyclin-dependent kinase inhibitor 1C (p57, Kip2)

Identifiers

Symbols

; BWCR; BWS; KIP2; WBS; p57; p57Kip2

External IDs

GeneCards:

Gene ontology
Molecular function	• •
Cellular component	• •
Biological process	• • • • • • • • • • • • • •
Sources: Amigo / QuickGO

RNA expression pattern

Orthologs

Species

Human

Mouse

Entrez

Ensembl

UniProt

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

PubMed search

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

1 Function
2 Clinical significance
3 Interactions
4 References
5 Further reading
6 External links

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.^[1]

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.

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.^[3] 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).^[4]

Interactions

Cyclin-dependent kinase inhibitor 1C has been shown to interact with MyoD,^[5] MYBL2,^[6] PCNA^[7] and LIMK1.^[8]

References

^ ^a ^b "Entrez Gene: CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2)".
^ Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ (March 1995). "p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene". Genes & Development 9 (6): 650–62.

^ 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 (October 1997). "New p57KIP2 mutations in Beckwith-Wiedemann syndrome". Human Genetics 100 (5-6): 681–3.

^ Riccio, Andrea; Cubellis, Maria Vittoria. "Gain of function in CDKN1C". Nature Genetics 44 (7): 737–738.

^ Reynaud, E G; Leibovitch M P; Tintignac L A; Pelpel K; Guillier M; Leibovitch S A (June 2000). "Stabilization of MyoD by direct binding to p57(Kip2)". J. Biol. Chem. (UNITED STATES) 275 (25): 18767–76.

^ Joaquin, Manel; Watson Roger J (November 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". J. Biol. Chem. (United States) 278 (45): 44255–64.

^ Watanabe, H; Pan Z Q; Schreiber-Agus N; DePinho R A; Hurwitz J; Xiong Y (February 1998). "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen".

^ Yokoo, Tomotaka; Toyoshima Hideo, Miura Mitsuhiro, Wang Yuhui, Iida Kaoruko Tada, Suzuki Hiroaki, Sone Hirohito, Shimano Hitoshi, Gotoda Takanari, Nishimori Shigeki, Tanaka Keiji, Yamada Nobuhiro (December 2003). "p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus". J. Biol. Chem. (United States) 278 (52): 52919–23.

Further reading

Seizinger BR (1992). "Genes associated with tumor suppression and growth control in the human nervous system.". Cancer Metastasis Rev. 10 (4): 281–7.

Lee MH, Reynisdóttir I, Massagué J (1995). "Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution.". Genes Dev. 9 (6): 639–49.

Matsuoka S, Edwards MC, Bai C, et al. (1995). "p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene.". Genes Dev. 9 (6): 650–62.

Matsuoka S, Thompson JS, Edwards MC, et al. (1996). "Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15.". Proc. Natl. Acad. Sci. U.S.A. 93 (7): 3026–30.

Reid LH, Crider-Miller SJ, West A, et al. (1996). "Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms' tumor assay.". Cancer Res. 56 (6): 1214–8.

Tokino T, Urano T, Furuhata T, et al. (1996). "Characterization of the human p57KIP2 gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis.". Hum. Genet. 97 (5): 625–31.

Hatada I, Ohashi H, Fukushima Y, et al. (1996). "An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome.". Nat. Genet. 14 (2): 171–3.

Furuhata T, Tokino T, Urano T, Nakamura Y (1997). "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.

LaBaer J, Garrett MD, Stevenson LF, et al. (1997). "New functional activities for the p21 family of CDK inhibitors.". Genes Dev. 11 (7): 847–62.

Watanabe H, Pan ZQ, Schreiber-Agus N, et al. (1998). "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen.". Proc. Natl. Acad. Sci. U.S.A. 95 (4): 1392–7.

Bhuiyan ZA, Yatsuki H, Sasaguri T, et al. (1999). "Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome.". Hum. Genet. 104 (3): 205–10.

Lam WW, Hatada I, Ohishi S, et al. (1999). "Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation.". J. Med. Genet. 36 (7): 518–23.

Reynaud EG, Leibovitch MP, Tintignac LA, et al. (2000). "Stabilization of MyoD by direct binding to p57(Kip2).". J. Biol. Chem. 275 (25): 18767–76.

Fink JR, LeBien TW (2001). "Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors.". Exp. Hematol. 29 (4): 490–8.

Kido K, Doerks A, Lochelt M, Flügel RM (2002). "Identification and functional characterization of an intragenic DNA binding site for the spumaretroviral trans-activator in the human p57Kip2 gene.". J. Biol. Chem. 277 (14): 12032–9.

Blint E, Phillips AC, Kozlov S, et al. (2002). "Induction of p57(KIP2) expression by p73beta.". Proc. Natl. Acad. Sci. U.S.A. 99 (6): 3529–34.

Ito Y, Yoshida H, Nakano K, et al. (2002). "Expression of p57/Kip2 protein in normal and neoplastic thyroid tissues.". Int. J. Mol. Med. 9 (4): 373–6.

Kikuchi T, Toyota M, Itoh F, et al. (2002). "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors.". Oncogene 21 (17): 2741–9.

Li Y, Nagai H, Ohno T, et al. (2002). "Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype.". Blood 100 (7): 2572–7.

External links

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

CDKN1C human gene location in the UCSC Genome Browser.

CDKN1C human gene details in the UCSC Genome Browser.

Cell cycle proteins

Cyclin

A (A1, A2)

B (B1, B2, B3)

D (D1, D2, D3)

E (E1, E2)

CDK

1

2

3

4

5

6

7

8

9

10

CDK-activating kinase

CDK inhibitor

INK4a/ARF (p14arf/p16, p15, p18, p19)

cip/kip (p21, p27, p57)

P53 p63 p73 family

p53

p63

p73

Other

Cdc2

Cdc25

Cdc42

Cellular apoptosis susceptibility protein

E2F

Maturation promoting factor

Wee

Cullin (CUL7)

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checkpoints

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Restriction point

Spindle checkpoint

Postreplication checkpoint

Other cellular phases

Apoptosis

G₀ phase

Meiosis

'' : dna

/

stru

Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes

Ligand

Growth factors

ONCO: c-Sis/PDGF

HGF

Receptor

Wnt signaling pathway

TSP: CDH1

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TSP: PTCH1

TGF beta signaling pathway

TSP: TGF beta receptor 2

Receptor tyrosine kinase

ONCO: ErbB/c-ErbB

HER2/neu

Her 3

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c-Ret

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ONCO: c-Kit

Flt3

Intracellular signaling P+Ps

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ONCO: Beta-catenin

TSP: APC

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SMAD4

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ONCO: c-Akt

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ONCO: c-Ras

HRAS

c-Raf

Other/unknown

TSP: Maspin

ONCO: c-Src

Nucleus

Cell cycle

TSP: p53

pRb

WT1

p16/p14arf

ONCO: CDK4

Cyclin D

Cyclin E

DNA repair/Fanconi

TSP: BRCA1

BRCA2

Ubiquitin ligase

TSP: VHL

ONCO: CBL

MDM2

Transcription factor

TSP: KLF6

ONCO: AP-1

c-Fos

c-Jun

c-Myc

Mitochondria

Apoptosis inhibitor: SDHB

SDHD

Other/ungrouped

c-Bcl-2 - Notch - Stathmin

: NEO

,

, ,

drug (//)

Categories

Human proteins

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Cyclin-dependent kinase inhibitor 1C