Cyclin-dependent kinase inhibitor 1C

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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]

## Contents

* 1 Function
* 2 Research Methods
* 3 Clinical significance
* 4 Interactions
* 5 References
* 6 Further reading
* 7 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.

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). Immuohistochemical 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]

## References

1. ↑ 1.0 1.1 "Entrez Gene: CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1028.
2. ↑ "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. doi:10.1101/gad.9.6.650. PMID 7729684.
3. ↑ "Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer". Nature Communications 12 (1): 4360. July 2021. doi:10.1038/s41467-021-24537-3. PMID 34272384. Bibcode: 2021NatCo..12.4360P.
4. ↑ "Epigenetics Impriting". University of California Berkeley. https://mcb.berkeley.edu/courses/mcb142/lecture topics/Amacher/LECTURE_13_Imprinting_F08.pdf.
5. ↑ "Linking DNA methylation and histone modification: patterns and paradigms". Nature Reviews. Genetics 10 (5): 295–304. May 2009. doi:10.1038/nrg2540. PMID 19308066.
6. ↑ "Sanger Sequencing Steps & Method". Merck KGaA. Darmstadt, Germany. https://www.sigmaaldrich.com/US/en/technical-documents/protocol/genomics/sequencing/sanger-sequencing.
7. ↑ "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. doi:10.1002/humu.22824. PMID 26077438.
8. ↑ "New p57KIP2 mutations in Beckwith-Wiedemann syndrome". Human Genetics 100 (5–6): 681–3. Oct 1997. doi:10.1007/s004390050573. PMID 9341892.
9. ↑ "Gain of function in CDKN1C". Nature Genetics 44 (7): 737–8. Jul 2012. doi:10.1038/ng.2336. PMID 22735584.
10. ↑ "Diagnosis of hydatidiform moles using p57 immunohistochemistry and HER2 fluorescent in situ hybridization". American Journal of Clinical Pathology 129 (5): 749–755. May 2008. doi:10.1309/7XRL378C22W7APBT. PMID 18426735.
11. ↑ "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. doi:10.1074/jbc.M309334200. PMID 14530263.
12. ↑ "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. doi:10.1074/jbc.M308953200. PMID 12947099.
13. ↑ "Stabilization of MyoD by direct binding to p57(Kip2)". The Journal of Biological Chemistry 275 (25): 18767–76. Jun 2000. doi:10.1074/jbc.M907412199. PMID 10764802.
14. ↑ "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. doi:10.1073/pnas.95.4.1392. PMID 9465025. Bibcode: 1998PNAS...95.1392W.

## Further reading

* "Genes associated with tumor suppression and growth control in the human nervous system". Cancer and Metastasis Reviews 10 (4): 281–7. Dec 1991. doi:10.1007/BF00554790. PMID 1786629.
* "Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution". Genes & Development 9 (6): 639–49. Mar 1995. doi:10.1101/gad.9.6.639. PMID 7729683.
* "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. doi:10.1101/gad.9.6.650. PMID 7729684.
* "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. doi:10.1073/pnas.93.7.3026. PMID 8610162. Bibcode: 1996PNAS...93.3026M.
* "Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms' tumor assay". Cancer Research 56 (6): 1214–8. Mar 1996. PMID 8640800.
* "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. doi:10.1007/BF02281873. PMID 8655143.
* "An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome". Nature Genetics 14 (2): 171–3. Oct 1996. doi:10.1038/ng1096-171. PMID 8841187.
* "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. PMID 8934543.
* "New functional activities for the p21 family of CDK inhibitors". Genes & Development 11 (7): 847–62. Apr 1997. doi:10.1101/gad.11.7.847. PMID 9106657.
* "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. doi:10.1073/pnas.95.4.1392. PMID 9465025. Bibcode: 1998PNAS...95.1392W.
* "Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome". Human Genetics 104 (3): 205–10. Mar 1999. doi:10.1007/s004390050937. PMID 10323243.
* "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. doi:10.1136/jmg.36.7.518. PMID 10424811.
* "Stabilization of MyoD by direct binding to p57(Kip2)". The Journal of Biological Chemistry 275 (25): 18767–76. Jun 2000. doi:10.1074/jbc.M907412199. PMID 10764802.
* "Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors". Experimental Hematology 29 (4): 490–8. Apr 2001. doi:10.1016/S0301-472X(01)00619-1. PMID 11301189.
* "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. doi:10.1074/jbc.M108747200. PMID 11815601.
* "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. doi:10.1073/pnas.062491899. PMID 11891335. Bibcode: 2002PNAS...99.3529B.
* "Expression of p57/Kip2 protein in normal and neoplastic thyroid tissues". International Journal of Molecular Medicine 9 (4): 373–6. Apr 2002. doi:10.3892/ijmm.9.4.373. PMID 11891530.
* "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors". Oncogene 21 (17): 2741–9. Apr 2002. doi:10.1038/sj.onc.1205376. PMID 11965547.
* "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. doi:10.1182/blood-2001-11-0026. PMID 12239171.

## 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.

* v
* t
* e

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)

Phases and
checkpoints|

| Interphase|

* G1 phase
* S phase
* G2 phase

|

M phase|

* Mitosis (Preprophase
* Prophase
* Prometaphase
* Metaphase
* Anaphase
* Telophase)
* Cytokinesis

Cell cycle checkpoints|

* Restriction point
* Spindle checkpoint
* Postreplication checkpoint

Other cellular phases|

* Apoptosis
* G0 phase
* Meiosis

* v
* t
* e

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

Ligand|

| Growth factors|

| ONCO|

* c-Sis/PDGF
* HGF

|

Receptor|

| Wnt signaling pathway|

| TSP|

* CDH1

|

Hedgehog signaling pathway|

| TSP|

* PTCH1

|

TGF beta signaling pathway|

| TSP|

* TGF beta receptor 2

|

Receptor tyrosine kinase|

| ONCO|

* ErbB/c-ErbB
* HER2/neu
* Her 3
* c-Met
* c-Ret

|

JAK-STAT signaling pathway|

| ONCO|

* c-Kit
* Flt3

|

Intracellular signaling P+Ps|

| Wnt signaling pathway|

| ONCO|

* Beta-catenin

|

TSP|

* APC

TGF beta signaling pathway|

| TSP|

* SMAD2
* SMAD4

|

Akt/PKB signaling pathway|

| ONCO|

* c-Akt

|

TSP|

* PTEN

Hippo signaling pathway|

| TSP|

* Neurofibromin 2/Merlin

|

MAPK/ERK pathway|

| ONCO|

* c-Ras
* HRAS
* c-Raf

|

TSP|

* Neurofibromin 1

Other/unknown|

| ONCO|

* c-Src

|

TSP|

* Maspin

Nucleus|

| Cell cycle|

| ONCO|

* CDK4
* Cyclin D
* Cyclin E

|

TSP|

* p53
* pRb
* WT1
* p16/p14arf

DNA repair/Fanconi|

| TSP|

* BRCA1
* BRCA2

|

Ubiquitin ligase|

| ONCO|

* CBL
* MDM2

|

TSP|

* VHL

Transcription factor|

| ONCO|

* AP-1
* c-Fos
* c-Jun
* c-Myc

|

TSP|

* KLF6

Mitochondrion|

| Apoptosis inhibitor|

* SDHB
* SDHD

|

Other/ungrouped|

* c-Bcl-2
* Notch
* Stathmin

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