Molecular mechanisms of retinoic acid-mediated control of cellular proliferation and differentiation

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By using the differential hybridization methods, we isolated the 20 kinds of cDNA clones, whose expression is induced during RA-mediated F9 cell differentiation. Focusing on the following two clones, we analyzed the structure and function of the genes.(1) Rae12 : the rae12 gene family encodes at least 5 kinds of different 14-3-3 protein members, whose expression is induced during RA-mediated F9 cell differentiation. We showed the expression of these members enhance the Raf-1 kinase. Furthermore, we demonstrated the following points : i) overexpression of 14-3-3 proteins enhances the signal transduction in the MAP kinase cascade, resulting in the stimulated cellular proliferation and tumorigenic transformation of NIH 3T3 cells. ii) the induced expression of 14-3-3 proteins enhances the signal transduction in the MAP kinase cascade, that plays an important role during RA-mediated F9 cell differentiation.(2) Rae28 : structure analysis the cDNA clone suggested that the rae28 gene is a mammalian homologue of a Drosophila polyhometic gene. We isolated the rae28 gene and established the rae28 knockout mice. The homozygotes are lethal and showed the following intriguing phenotypes : i) heart malformations, ii) ophthalmic abnormalities, iii) skeletal abnormalities (posterior transformation) , iv) cleft palate.