Induction of cyclin D1 by simian virus 40 small tumor antigen

Abstract

Cell-cycle progression is mediated by a coordinated interaction between cyclin-dependent kinases and their target proteins including the pRB and E2F͞DP-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-1 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 D1 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 (stressactivated 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.

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

“…(2) PP2A represses AP-1 activity by dephosphorylation of c-Jun on Ser-63 (Alberts et al, 1993;AlMurrani et al, 1999;Ramirez et al, 2005). (3) c-Jun enhances cell proliferation through induction of cyclin D1 transcription, shown by several reports (Watanabe et al, 1996;Shiozawa et al, 2004;Whang et al, 2005). The possibility that the involvement of c-Jun in the mechanism of LMB-induced reduction of cyclin D1 expression was further supported by our findings: (1) serum-induced cyclin D1 expression is required for AP-1 site in the promoter region of cyclin D1 gene, and the residual promoter activity of AP-1 site-deleted or pointmutated cyclin D1 promoter construct is no longer inhibited by LMB treatment.…”

“…The reporter constructs of the human cyclin D1 promoter were a gift from Richard G Pestell (Watanabe et al, 1996;Albanese et al, 1999). A 1745-bp fragment of the human cyclin D1 gene was obtained by polymerase chain reaction (PCR) and cloned into the plasmid pGL3-Basic (Promega, Madison, MA, USA) to generate -1745D1LUC.…”

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

“…Accumulation of this complex leads to the activation of the kinases that phosphorylate and inactivate the tumor suppressor retinoblastoma, a necessary step for cell cycle progression through G1-to-S phases (Harbour and Dean, 2000). The expression levels of cyclin D1 have been shown to be rate limiting in cellular proliferation induced by a variety of stimuli (Ohtsubo and Roberts, 1993;Quelle et al, 1993;Albanese et al, 1995;Watanabe et al, 1996), and an increased expression of cyclin D1 has been observed in several tumors (Wang et al, 1994;Arber et al, 1996;Zhang et al, 1997;Albanese et al, 1999).…”

Truncated N-terminal mutants of SV40 large T antigen as minimal immortalizing agents for CNS cells

“…Known cellular targets for small t are hsc70 (Srinivasan et al, 1997) and protein phosphatase 2A (Pallas et al, 1990;Yang et al, 1991). Other reported functions of small t include transcriptional activation of promoters of AP-1 (Frost et al, 1994) cyclin A (Porras et al, 1999), and cyclin D1 (Watanabe et al, 1996), repression of c-fos promoters (Wang et al, 1994), and down-regulation of the cdk inhibitor p27 KIP1 (Porras et al, 1999).…”