Reduced growth factor requirements and accelerated cell-cycle kinetics in adult human melanocytes transformed with SV40 large T antigen.
Melanomas develop with high frequency in transgenic mice in which oncogenic sequences of the SV40 DNA tumor virus have been specifically targeted to melanocytes. To investigate the role of SV40 in melanomagenesis, cultured human melanocytes were transformed with a retroviral shuttle vector encoding the SV40 large T antigen and examined for changes in cell-cycle kinetics and growth-factor dependence. Colonies expressing the viral oncogene were morphologically indistinguishable from their non-T-antigen-transformed counterparts. Also like normal melanocytes, the infected cells remained anchorage dependent and non-tumorigenic in nude mice. However, T-antigen-positive cultures exhibited significantly accelerated population doubling times, increased saturation densities with highly confluent monolayers and a three- to fourfold extended life span. Most interestingly, cell-cycle analysis revealed a measurable shift from quiescent to cycling cells in T-antigen-expressing cultures and an acquired ability to progress more rapidly through G1. Moreover, T-antigen-positive melanocytes proliferated in the absence of PMA and required markedly reduced levels of exogenous bFGF. These studies indicate that the viral oncogen of simian virus 40 provides melanocytes with distinct growth advantages that may render these cells unusually susceptible to additional environmental challenges necessary for full expression of the malignant phenotype.
Zepter
K
K
Department of Dermatology and Skin Diseases Research Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Häffner
A C
AC
Trefzer
U
U
Elmets
C A
CA
D000328:Adult; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D002453:Cell Cycle; D002461:Cell Line, Transformed; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000276:immunology*; D008545:Melanoma / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D016222:Fibroblast Growth Factor 2