Induction of cyclin D1 by simian virus 40 small tumor antigen

Cell-cycle progression is mediated by a coordinated interaction between cyclin-dependent kinases and their target proteins including the pRB and E2F/DP-1 complexes. Immunoneutralization and antisense experiments have established that the abundance of cyclin D1, a regulatory subunit of the cyclin-dependent kinases, may be rate-limiting for G(1) phase progression of the cell cycle. Simian virus 40 (SV40) small tumor (t) antigen is capable of promoting G(1) phase progression and augments substantially the efficiency of SV40 transformation through several distinct domains, In these studies, small t antigen stimulated cyclin D1 promoter activity 7-fold, primarily through an AP-1 binding site at -954 with additional contributions from a CRE site at -57. The cyclin D1 AP-I and CRE sites were sufficient for activation by small t antigen when linked to an heterologous promoter, Point mutations of small t antigen between residues 97-103 that reduced PP2A binding were partially defective in the induction of the cyclin DI promoter, These mutations also reduced activation of MEK1 and two distinct members of the mitogen-activated protein kinase family, the ERKs (extracellular signal regulated kinases) and the SAPKs (stress activated protein kinases), in transfected cells, Dominant negative mutants of either MEK1, ERK or SEK1, reduced small t-dependent induction of the cyclin D1 promoter, SV40 small t induction of the cyclin D1 promoter involves both the ERK and SAPK pathways that together may contribute to the proliferative and transformation enhancing activity of small t antigen.