Akoulitchev, Alexandre Victor; (1994) Synergistic regulation of cdc2 and cyclin A gene transcription by co-operating oncogenes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Co-operative transformation of Schwann cells and rat embryo fibroblasts by oncogenic ras and the viral oncoproteins SV40 large T, or Adenovirus El A is accompanied by synergistic regulation of specific cell cycle regulatory genes. For example, in Schwann cells, ras inhibits proliferation, and as a prerequisite for the growth arrest, inhibits expression of cell cycle regulators such as cyclin A and cdc2. In contrast, in cells fully transformed by ras and large T (or E1A) the same cell cycle regulators are over-expressed. In transfection experiments it was shown that ras and E1A regulate transcription of the cdc2 and cyclin A genes. In proliferating cells the activities of the cdc2 and cyclin A promoters are suppressed up to tenfold by the ras oncogene. E1A can activate the same promoters in mitogen-starved cells. Moreover, together ras and E1A synergistically stimulate both promoters in contact-inhibited cells. All three types of regulation are mediated by distinct promoter elements which are conserved in both cdc2 and cyclin A promoters and are sufficient to confer the oncogene-induced responses. Possible mechanisms involved in the regulation through these elements are investigated and discussed. The synergistic regulation of cell cycle gene transcription by co-operating oncogenes not only provides a link between growth control signals and the cell cycle, but also shows that distinct oncogene-induced signals converge on common targets. Such signal integration processes may at least in part explain the synergistic nature of oncogene co-operation in cell transformation.

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