F-box protein Skp2: a novel transcriptional target of E2F

Abstract

The F-box-containing protein Skp2 plays a critical role in coordinating the G1/S transition and progression through the S phase of the mammalian cell cycle. Skp2 is overexpressed in a broad spectrum of human cancers and the expression level correlates with tumor malignancy. However, the Skp2 gene is neither amplified nor rearranged in most human cancers and the underlying mechanism of Skp2 overexpression remains poorly understood. We show here that the Skp2 gene contains a functional E2F response element (hSRE2). Ectopic expression of E2F1 induces expression of the endogenous Skp2 gene in human fibroblast cells, whereas antisensemediated knockdown of E2F1 in human tumor cell lines reduces expression of endogenous Skp2 gene. The hSRE2 element not only participates in activation of Skp2 promoter function during normal cell cycle progression into S phase, it is also required for the high-level Skp2 gene expression in many human tumor cell lines. These results reveal Skp2 as a novel target for E2F regulation that is disrupted in several human tumor cell lines.

Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells

“…However, the transactivating mechanisms for Skp2 promoter activation may be stimulus-and cell-specific, and it is possible that additional transcriptional mechanisms act in concert to induce transcription of the Skp2 gene. For example, in fibroblasts and cancer cells Skp2 transcription has been demonstrated to involve a cell cycledependent activation of its promoter by GA-binding proteins or E2F transcription factors, respectively (23,31). Although our studies clearly support a key role of a direct NBRE-dependent transactivation of the Skp2 promoter by NOR1, indirect mechanisms may contribute to the increase in Skp2 transcript levels following NOR1 overexpression.…”

Hormonal induction of adipogenesis induces Skp2 expression through PI3K and MAPK pathways

“…In direct contrast to the above report, others have demonstrated that serial deletions of the 5 0 flanking region (À3,723 to þ212) of the human Skp2 promoter down to À59, which included the GABP binding site, had little effect on reporter activity in asynchronously proliferating HeLa cells [Zhang and Wang, 2005]. Surprisingly, however, 3 0 deletions resulted in a dramatic fall in activity leading to the identification of a required element between þ65 and þ149.…”

“…Recent evidence has demonstrated Skp2 expression to be upregulated in many cancer cells and to exhibit periodic regulation during normal cell-cycle progression through transcriptional [Imaki et al, 2003;Sarmento et al, 2005;Zhang and Wang, 2005] as well as protein degradation mechanisms [Wirbelauer et al, 2000;Zhang et al, 2003;Bashir et al, 2004;Wei et al, 2004] in a cell type specific manner. In neoplastic cells, Skp2 is upregulated by PI3K [Mamillapalli et al, 2001;Andreu et al, 2005] and negatively regulated by TGFb [Wang et al, 2004].…”

A reciprocal relationship between Rb and Skp2: implications for restriction point control, signal transduction to the cell cycle, and cancer

“…Zhang and Wang then reported that the human Skp2 promoter is regulated by a non-canonical E2F site in its promoter. 6 We performed an in silico analysis of conserved promoter motifs in several mammalian Skp2 promoters and found a distinct E2F site that is well conserved and closely related to the E2F consensus DNA binding sequence. 7 This conserved site also exists in the human promoter, and it is the only E2F site we could find in the mouse Skp2 promoter (at least within 3 kb bases upstream of the transcription start).…”