Keratinocytes blocked in phorbol ester-responsive early stage of terminal differentiation by sarcoma viruses

It has been suggested that the initiation step in mouse skin carcinogenesis involves an alteration in epidermal-differentiation, as mouse basal keratinocytes exposed to initiators resist the arrest of cell growth that is normally associated with the induction of terminal differentiation by calcium ions. The growth of epidermal basal cells infected by Kirsten (Ki) or Harvey (Ha) sarcoma viruses is, however, arrested in response to calcium ions, although the cells do not progress through their entire maturation programme when a functioning ras gene of those viruses is expressed. If continuous proliferation in the differentiating cell layers is a requirement for tumour formation in skin, the response of sarcoma virus-infected cells seems inconsistent with the suggestion that an activated ras gene is sufficient to initiate skin carcinogenesis. We now show that sarcoma virus-infected keratinocytes, when induced to differentiate, are blocked at an early, reversible stage of maturation. Furthermore, the cells respond to phorbol ester tumour promoters by undergoing a phenotypic reversion to a less mature stage. These results suggest that activation of a ras gene can produce conditionally initiated cells, in which the full expression of tumorigenicity depends on exposure to tumour promoters.