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Review
. 2018 Apr 2;19(4):1055.
doi: 10.3390/ijms19041055.

Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases

Emanuela Stampone  1 , Ilaria Caldarelli  2 , Alberto Zullo  3   4 , Debora Bencivenga  5 , Francesco Paolo Mancini  6 , Fulvio Della Ragione  7 , Adriana Borriello  8
Affiliations
Review

Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases

Emanuela Stampone et al. Int J Mol Sci. .

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.

Keywords: CDKN1C; cell differentiation; disease; epigenetics; p57Kip2.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of human 11p15.5 locus, CDKN1C gene, p57Kip2 mRNA and p57Kip2 protein. Panel (A) The panel shows the structure of the 11p15.5 locus with details of the KCNQ1 exon organization (in blue boxes). KCNQ1OT1 gene is included in the KCNQ1 gene and transcribed in a different direction. The ICR2 region is shown in orange; Panel (B) The figure shows the structure of CDKN1C gene and p57Kip2 mRNA. In addition, at the bottom of the figure, it is represented the domain organization of p57Kip2 protein and the sequence of the KID (kinase inhibitory domain).
Figure 1
Figure 1
Structure of human 11p15.5 locus, CDKN1C gene, p57Kip2 mRNA and p57Kip2 protein. Panel (A) The panel shows the structure of the 11p15.5 locus with details of the KCNQ1 exon organization (in blue boxes). KCNQ1OT1 gene is included in the KCNQ1 gene and transcribed in a different direction. The ICR2 region is shown in orange; Panel (B) The figure shows the structure of CDKN1C gene and p57Kip2 mRNA. In addition, at the bottom of the figure, it is represented the domain organization of p57Kip2 protein and the sequence of the KID (kinase inhibitory domain).
Figure 2
Figure 2
CDKN1C gene alterations in hereditary syndromes and human cancers. The figure reports on the left the Syndromes in which the CDKN1C gene is altered with the description of genotype alterations and main phenotypic features. On the right are reported the cancers showing CDKN1C genetic changes. IC1, ICR1 region; IC2, ICR2 region; GoM, gain of methylation; LoM, loss of methylation; UPD, Uniparental disomy.
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