Cell cycle progression is driven by the coordinated regulation of the activities of cyclin-dependent kinases (Cdks). Of the several mechanisms known to regulate Cdk activity in response to external signals, regulation of cyclin gene expression, post-translational modification of Cdks by phosphorylation-dephosphorylation cascades, and the interaction of cyclin/Cdk complexes with protein inhibitors have been thoroughly studied. During recent years, much attention has also been given to mechanisms that regulate protein degradation by the ubiquitin/proteasome pathway, as well as to the regulation of subcellular localization of the proteins that comprise the intrinsic cell cycle clock. The purpose of the present review is to summarize the most important aspects of the various mechanisms implicated in cell cycle regulation.

Nucleostemin (NS) encodes a nucleolar GTPase which is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of NS expression. Here we identify NS as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B-cells from Eμ-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin IP we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/−Eμ-myc transgenics have indeed much slower rates of B cell lymphoma development, with life spans twice that of wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells both in vitro and in vivo. Impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B-cells. Finally, we provide evidence that NS control cultured cell proliferation independently of p53 and that NS haploinsufficiency significantly delayed lymphomagenesis on a p53-deficient background. Together these data indicate that NS functions, downstream of Myc, as a rate limiting factor for the proliferation and transformation of cells independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.

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