DEVELOPMENTALLY-REGULATED EXPRESSION OF MURINE K-RAS ISOFORMS

The products (p21) of the three mammalian H-, N- and K-ras genes play important roles in intracellular signal transduction, linking membrane receptor kinases to the nuclear pathway through raf and mitogen activ ated protein kinase. They are involved in the regulation of proliferat ion and differentiation, and activating mutations of these genes are c ommonly associated with human cancers. Two p21 proteins are encoded by the K-ras gene (p21(K-rasA) and p21(K-rasB)) due to alternative splic ing of the fast exon. While the four p21(ras) proteins are highly homo logous, their sequences diverge significantly at the C-termini, to whi ch distinct biochemical and perhaps even functional differences may be ascribed. However, H-, N- and K-rasB appear to be ubiquitously expres sed, with little evidence of tissue-specific or developmental regulati on. In contrast, we now demonstrate that the expression of K-rasA is s trikingly different, K-rasA is induced during differentiation of pluri potent embryonal stem cells in vitro. Its expression during early embr yogenesis is limited temporally and spatially in a tissue-specific dis tribution which is largely maintained as an adult. This suggests a dis tinct biological role for p21(K-rasA).