P57^Kip2 is a cyclin-dependent kinase inhibitor belonging to the Cip/Kip family, which also includes p21^Cip1 and p27^Kip1. So far, p57^Kip2 is the least-studied Cip/Kip protein, and for a long time its relevance has been related mainly to its unique role in embryogenesis. Moreover, genetic and molecular studies on animal models and patients with Beckwith-Wiedemann syndrome have shown that alterations in CDKN1C (the p57^Kip2 encoding gene) have functional relevance in the pathogenesis of this disease. Recently, a number of investigations have identified and characterized heretofore unexpected roles for p57^Kip2. The protein appears to be critically involved in initial steps of cell and tissue differentiation, and particularly in neuronal development and erythropoiesis. Intriguingly, p27^Kip1, the Cip/Kip member that is most homologous to p57^Kip2, is primarily involved in the process of cell cycle exit. p57^Kip2 also plays a critical role in controlling cytoskeletal organization and cell migration through its interaction with LIMK-1. Furthermore, p57^Kip2 appears to modulate genome expression. Finally, accumulating evidence indicates that p57^Kip2 protein is frequently downregulated in different types of human epithelial and nonepithelial cancers as a consequence of genetic and epigenetic events. In summary, the emerging picture is that several aspects of p57^Kip2's functions are only poorly clarified. This review represents an appraisal of the data available on the p57^Kip2 gene and protein structure, and its role in human physiology and pathology. We particularly focus our attention on p57^Kip2 changes in cancers and pharmacological approaches for modulating p57^Kip2 levels. Mol Cancer Res; 9(10); 1269–84. ©2011 AACR.

The CDKN1C gene encodes the p57^Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27^Kip1 and p21^Cip1. In analogy with these proteins, p57^Kip2 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 p57^Kip2 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 p57^Kip2 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 p57^Kip2 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 p57^Kip2 protein are briefly described and correlated to human physiology and diseases.

Introduction: Cell division cycle progression is achieved by a sequential and stringently concerted activation of a family of serine–threonine kinases, namely the cyclin-dependent kinases (CDKs). p27^Kip1 is a pivotal CDK inhibitor and a tight modulator of CDK-dependent phenotypes. Thus, p27^Kip1 plays a fundamental role in key cellular processes such as proliferation, differentiation, apoptosis, substrate adhesion and motility. Intriguingly, when p27^Kip1 is localized in the nucleus, it acts as an antiproliferative protein, while, in the cytosol, p27^Kip1 promotes cytoskeleton remodeling and might positively influence metastatization. Downregulation of p27^Kip1 nuclear level or its cytosolic mislocalization are consistently correlated with poor prognosis of numerous types of human epithelial and non-epithelial cancers. Areas covered: This review illustrates the basic structural features of p27^Kip1 protein, its metabolism and alterations in human malignancies, along with describing anticancer strategies based on targeting p27^Kip1. Expert opinion: Given the role of p27^Kip1 in the control of cell proliferation and its decreased level observed in malignancies with poor outcome, drugs able to handle the protein levels and localization might represent an important goal for novel specific and effective anticancer strategies. Although no convincing proofs have been reported, putative negative consequences of p27^Kip1 targeting might be also conceivable.

Mutations in VHL, which encodes von Hippel–Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL–hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.)