Functional Versatility of the CDK Inhibitor p57Kip2

Abstract

The cyclin/CDK inhibitor p57^Kip2 belongs to the Cip/Kip family, with p21^Cip1 and p27^Kip1, and is the least studied member of the family. Unlike the other family members, p57^Kip2 has a unique role during embryogenesis and is the only CDK inhibitor required for embryonic development. p57^Kip2 is encoded by the imprinted gene CDKN1C, which is the gene most frequently silenced or mutated in the genetic disorder Beckwith-Wiedemann syndrome (BWS), characterized by multiple developmental anomalies. Although initially identified as a cell cycle inhibitor based on its homology to other Cip/Kip family proteins, multiple novel functions have been ascribed to p57^Kip2 in recent years that participate in the control of various cellular processes, including apoptosis, migration and transcription. Here, we will review our current knowledge on p57^Kip2 structure, regulation, and its diverse functions during development and homeostasis, as well as its potential implication in the development of various pathologies, including cancer.

Keywords: CDK inhibitor; CDKN1C; cell cycle; development; p57Kip2; stem cells; transcription.

FIGURE 1

Imprinting control of the 11p15.5 locus. The 11p15.5 locus is organized in two domains, telomeric and centromeric, each controlled by an imprinting control region (ICR). Imprinting of the telomeric region is controlled by ICR1, which allows repression of H19 and expression of IGF2 on the paternal allele, and reciprocal expression on the maternal allele. ICR2 controls imprinting of the centromeric domain. Methylation of ICR2 leads to the suppression of the LIT1 antisense RNA of the KCNQ1OT1 locus, allowing the expression of p57 from the maternal allele.

FIGURE 2

Structure of the p57^Kip2 protein. Cip/Kip proteins are highly conserved in their N-terminal domain that mediates binding to cyclins and CDKs, but diverge in their C-terminal part. Nevertheless, the C-terminus of p57 presents some homology with p21 (PCNA binding domain) and p27 (QT motif). Murine and human p57 are conserved in their N- and C-terminal domains but the central domains (II and III) in mice are substituted by a unique PAPA domain in human (II). The N-terminal CDK binding/inhibitory domain (KID) of p57 is subdivided in three domains: a cyclin binding domain (1), a CDK binding domain (2) and a 3₁₀ helix (3). The C-terminal QT domain (238–316) of p57 presents strong homology to the p27 QT motif at amino acids 302–316. It also contains three other conserved motifs: a PCNA binding domain (272–297) similar to p21, a nuclear localization signal (NLS, 278–281), and a CDK phosphorylation site (T310). Through its diverse domains p57 is able to interact with multiple partners involved in numerous cellular process, such as MyoD, b-Myb, LIMK1, PCNA, or JNK.