Transcriptional regulation of i p57 sup kip2 sup i expression during development differentiation and disease

Abstract

p57 is the most complex member of the CIP/KIP family of cyclin-dependent kinase inhibitors and plays a fundamental role in regulating cell cycle and differentiation during mammalian development. Consistently with a key role for p57 in the spatial and temporal control of cell proliferation, its expression is fine-tuned by multiple regulatory mechanisms, resulting in a tissue-, developmental phase- and cell type-specific pattern. Moreover, is an imprinted gene, further supporting the importance of its proper expression dosage. Importantly, misregulation of expression has been associated, more frequently than mutations in its coding region, to human growth disorders, such as Beckwith-Wiedemann and Silver-Russell syndromes, as well as to the onset of several types of cancers. This review will summarize the molecular mechanisms regulating transcription during differentiation and development, their relationship with the imprinting control and their alterations in growth-related diseases and cancer. Particular attention will be given to the role of epigenetic mechanisms, involving DNA methylation, histone modifications, long-range chromatin interactions and non-coding RNAs in modulating and integrating the functions of cis-regulatory elements and trans-acting factors.

The long non-coding RNA Kcnq1ot1 controls maternal p57 expression in muscle cells by promoting H3K27me3 accumulation to an intragenic MyoD-binding region

“…Consistent with the critical importance of the proper p57 expression dosage, not only the paternal allele is ubiquitously and permanently silenced, but also the maternal allele is tightly and finely regulated during development and differentiation [16]. Our work in muscle cells revealed that KvDMR1, in addition to control the silencing of the imprinted p57 paternal allele, is also involved in preventing the expression of the functional p57 maternal allele until differentiation occurs [17, 18].…”

Methylation of Cdkn1c may be involved in the regulation of tooth development through cell cycle inhibition

“…Preodontoblasts are the polarized cells beginning to stop their proliferation and acquire differentiation, while mature odontoblasts are matrix-producing cells with their differention almost completed. It is generally thought that there exists an inverse relationship between cell proliferation and differentiation, and p57 is a cell cycle arrest gene and is associated with exit from the cell cycle and entry into differentiation (Rossi et al 2018 ). Thus it is explicable that we observed intensely p57 expression in immature odontoblasts, and reduced expression in mature odontoblasts (Fig.…”

A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57Kip2

“…The protein was identified by sequence homology with the other two members of the family, i.e., p21 Cip1/WAF1 and p27 Kip1 [1,2]. Differently from p21 Cip1/WAF1 and p27 Kip1 , scarce information has been accumulated on p57 structural characteristics despite more than 25 years having passed since its initial identification [3][4][5][6][7][8]. Certainly, what has definitely been demonstrated is that all CIP/Kip members present some structural features that are necessary to exert their function in the regulation of the cell division cycle.…”

“…Besides this inhibitory activity, p57 and its siblings have been reported as being able to promote the assembly of the Cyclin D-CDK4/6 complex, a striking characteristic that allows them to be considered more comprehensively as major cell cycle regulators [6][7][8][9]. The N-terminal domain is also involved in the interaction with transcription factors such as b-Myb and MyoD, controlling gene expression [5]. In contrast, they exhibit strongly divergent central and carboxy-terminal domains.…”