Cyclin-dependent kinase inhibitor 1C

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

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. 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.

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. 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.

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. 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. 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. 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). 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.

Interactions
Cyclin-dependent kinase inhibitor 1C has been shown to interact with:
 * LIMK1,
 * MYBL2,
 * MyoD, and
 * PCNA.