Altered Regulation of TGF‐β1 and TGF‐α in Primary Keratinocytes and Papillomas Expressing v‐Ha‐ras

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Abstract
The influence of an oncogenic v-Ha-ras gene on the expression of TGF-β and TGF-α by mouse keratinocytes and derived tumors has been investigated. Normal mouse keratinocytes cultured as basal cells in 0.05 mM Ca2+ secreted low levels of TGF-β2 peptide, and this increased markedly following culture in 1.4 mM Ca2+, retinoic acid, or phorbol esters. In contrast, introduction of a v-Ha-ras gene into normal keratinocytes increased basal expression and secretion of TGF-β1 (rather than TGF-β2) in response to all three agents. The selective secretion of TGF-β1 in v-Ha-ras keratinocytes in response to 1.4 mM Ca2+ occurred even though the four TGF-β2 transcripts were induced and the TGF-β1 transcript decreased, suggesting that the activated v-Ha-ras gene product regulates expression of the TGF-β isoforms at the posttranscriptional level. Immunohistochemical analysis of papillomas formed following skin grafting of v-Ha-ras keratinocytes onto nude mice indicated that TGF-β1 was abundant in the basal and spinous layers, while there was no expression of TGF-β1 in normal skin. In contrast, both normal and neoplastic tissues expressed TGF-β2 and TGF-β3 in the granular layers. Furthermore, TGF-α mRNA expression was also elevated fivefold in cultured v-Ha-ras keratinocytes, and TGF-α protein was overexpressed in the grafted papillomas, but there was no detectable expression in normal skin. Elevated expression of both TGF-β1 and TGF-α in the basal and spinous layers of benign tumors may be important for the high proliferation rate in these tumors as well as for increased proliferation in the suprabasal layer.