G-ALPHA(12) AND G-ALPHA(13) MEDIATE DIFFERENTIATION OF P19 MOUSE EMBRYONAL CARCINOMA-CELLS IN RESPONSE TO RETINOIC ACID

P19 mouse embryonal carcinoma cells can be stimulated to differentiate into endodermal-like, mesodermal-like, and neuronal-like phenotypes i n response to specific morphogens. At low concentrations, retinoic aci d stimulates P19 embryonal cells to differentiate to cells displaying an endodermal phenotype, whereas at higher concentrations it stimulate s differentiation to neuroectoderm, The G alpha(12) and G alpha(13) su bunits of heterotrimeric G-proteins are expressed in the embryonal P19 cells and stimulated in response to retinoic acid as the cells differ entiate to endodermal or neuroectodermal phenotypes, Suppression of th e expression of either G alpha(12) or G alpha(13) by antisense RNA is shown to promote cell detachment from substratum and apoptosis, Expres sion of the constitutively active, mutant form of Ga-12 (Q229L), in co ntrast, stimulates loss of the embryonal phenotype, Expression of the constitutively active form of G alpha(13) (Q226L) stimulates different iation of the cells from embryonal to endodermal, in the absence of re tinoic acid. Thus, both Ga-12 and Ga-13 are essential to stimulation o f cell differentiation by retinoic acid, Deficiency of either G alpha( 12) or G alpha(13) increases programmed cell death.