Transcriptional regulation of p57 expression during development, differentiation and disease

p57^kip2 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^kip2 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, p57 is an imprinted gene, further supporting the importance of its proper expression dosage. Importantly, misregulation of p57 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 p57 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.