ras activity and cyclin D1 expression: An essential mechanism of mouse skin tumor development

Abstract

ras is a family of small GTP-binding proteins that transduce signals from tyrosine-kinase receptors to the nucleus and thus play a role in the regulation of cell proliferation and differentiation. Several lines of evidence have shown that the cell-cycle machinery, specifically the circuit cyclin D1/cyclin-dependent kinase (cdk) 4 and 6-p16-pRb, lies downstream of ras. Point mutations that activate the ras protein and its downstream cascade have been observed in human and experimental tumors. In particular, ras mutations have been well characterized in the mouse skin two-stage carcinogenesis model, and a large body of literature has indicated that initiation with the genotoxic carcinogen 7,12-dimethylbenz[a]anthracene induces a specific point mutation in Ha-ras gene in this model. In the last few years, several studies have shown a correlation between ras activation and alterations in the expression of cyclin D1 as well as other cell cycle-regulated proteins, but the actual role of these alterations in tumor development had not been determined until a recent study provided genetic and biochemical evidence that cyclin D1 is a critical target of oncogenic ras in mouse skin carcinogenesis. Here we review these results, including the evidence that cyclin D1 has a role as a downstream mediator of ras activity during tumor development. We propose a model in which cyclin D1 has a unique growth-promoting role in tumor development but does not act as an oncogene independently of ras activity.

Protection against human papillomavirus type 16‐E7 oncogene‐induced tumorigenesis by in vivo expression of dominant‐negative c‐jun†

“…The ras‐MAPK pathway can regulate the cell cycle through cyclin/cyclin‐dependent kinase complexes. Specifically, activation of the ras‐MAPK pathway produces an increase in cyclin D1 expression [14]. Furthermore, MAPK activation of cyclin D1 expression requires an intact AP‐1 site in its promoter [15, 16].…”

“…Cyclin D1–deficient mice are protected from ras‐mediated (including DMBA/TPA‐induced) tumorigenesis [19], while cyclin D1 transgenics show no enhancement of skin tumor development [20]. These results indicate that cyclin D1 activation is essential but not sufficient for tumor promotion [14]. Because (1) cyclin D1 expression is seen in premalignant lesions and not in normal or hyperproliferating keratinocytes, (2) loss of cyclin D1 expression protects mice from tumorigenesis, and (3) cyclin D1 expression is regulated by AP‐1, it seems probable that the protective action of DN c‐jun involves blocking AP‐1‐regulated expression of cyclin D1 in premalignant cells.…”

c-Jun/AP-1 pathway-mediated cyclin D1 expression participates in low dose arsenite-induced transformation in mouse epidermal JB6 Cl41 cells

“…Cyclin D proteins are regulators of G1 to S phase transitions, and they bind to cyclin-dependent kinase 4 (CDK4) and increase its kinase activity, thereby causing the phosphorylation and inactivation of the retino-blastoma tumor suppressor protein (Shaulian and Karin, 2001; Sherr, 1996). Aberrant cyclin D1 expression has been observed in carcinogenesis (Barnes and Gillett, 1998; Fusenig and Boukamp, 1998; Weinstein, 2000), and overexpression of cyclin D1 was reported in several human cancers, including skin cancer (Rodriguez-Puebla et al, 1999). Previous studies have shown that the human cyclin D1 gene regulatory sequences contain two AP-1 binding sites (Albanese et al, 1995; Herber et al, 1994; Shaulian and Karin, 2001).…”

A mouse model of human oral-esophageal cancer

“…Cooperation by cyclin D1 with other genetic alterations is essential for tumor formation in mouse models. Thus, cyclin D1 and c-myc induce lymphomas, and cyclin D1 and ras generate skin tumors in mice (23,24,30,31).…”