Abstract
The CDKN1C gene encodes the p57Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27Kip1 and p21Cip1. In analogy with these proteins, p57Kip2 is able to bind tightly and inhibit cyclin/cyclin-dependent kinase complexes and, in turn, modulate cell division cycle progression. For a long time, the main function of p57Kip2 has been associated only to correct embryogenesis, since CDKN1C-ablated mice are not vital. Accordingly, it has been demonstrated that CDKN1C alterations cause three human hereditary syndromes, characterized by altered growth rate. Subsequently, the p57Kip2 role in several cell phenotypes has been clearly assessed as well as its down-regulation in human cancers. CDKN1C lies in a genetic locus, 11p15.5, characterized by a remarkable regional imprinting that results in the transcription of only the maternal allele. The control of CDKN1C transcription is also linked to additional mechanisms, including DNA methylation and specific histone methylation/acetylation. Finally, long non-coding RNAs and miRNAs appear to play important roles in controlling p57Kip2 levels. This review mostly represents an appraisal of the available data regarding the control of CDKN1C gene expression. In addition, the structure and function of p57Kip2 protein are briefly described and correlated to human physiology and diseases.
Highlights
A well-orchestrated sequence of events allows the transition between the various phases of cell division cycle and the precise control of a perfect execution and accomplishment of each phase
We provide an appraisal of the published data on the p57Kip2 protein, that represents the least studied member within the CIP/Kip family
Cancer cells with low p57Kip2 present histone hypoacetylation and, vice versa, tumors with a high level of the CDK inhibitors (CKI) show hyperacetylation [109,110]. These findings are confirmed by the re-expression of p57Kip2 after histone deacetylase (HDAC) inhibitor treatment [76]
Summary
A well-orchestrated sequence of events allows the transition between the various phases of cell division cycle and the precise control of a perfect execution and accomplishment of each phase. The tissue-specific functions of p57Kip cannot be substituted by other CIP/Kip family members, suggesting that each of them has peculiar roles in cell physiology. P27Kip1knock-in corrected many of the abnormalities observed in p57KO mice, except for omphalocele, dysplasia of placenta and renal papilla [34] This evidence supported the opinion that most of the functions performed by both p27Kip and p57Kip proteins during development are attributable to the CKI role through their conserved N-terminal KID domain. All the three CIP/Kip proteins are expressed in terminally differentiated cells, but, of great interest, in certain undifferentiated quiescent stem cells, probably because of their CKI activity. The general picture is complex and difficult to understand due to the cross-talk and overlapping of different signal pathways
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