THE G-PROTEIN G(I) REGULATES MITOSIS BUT NOT DNA-SYNTHESIS IN GROWTH FACTOR-ACTIVATED FIBROBLASTS - A ROLE FOR THE NUCLEAR TRANSLOCATION OFG(I)

GTP binding proteins, heterotrimeric molecules composed of alpha-, bet a-, and gamma-subunits, are known to serve as transducers of informati on from seven-transmembrane receptors, Activation of G-proteins has be en generally considered to involve subunit dissociation, with G(alpha) separating from G(beta gamma). However, we have found a receptor acti vation of G(i) in proliferating cells that differs from these models a nd involves the subcellular translocation of the alpha-subunit from th e cell periphery to tile nucleus where G(i alpha) binds to chromatin f or the duration of mitosis, This report describes the mechanism of G(i ) activation in Swiss 3T3 cells in response to serum, thrombin, and ep idermal growth factor, and describes a role for G(i2) in the cell cycl e, Agonists were found to be unable to induce the physical dissociatio n of G(i2) subunits, The alpha- and beta-subunits of G(i2) could be co immunoprecipitated with a G(i alpha) antibody from both the membrane a nd nuclear fractions of long-term activated cultures, showing that G(i alpha 2) and G(i beta) are induced to comigrate to the nucleus in res ponse to growth factor receptor activation, G(i2) appears to be activa ted in part by a postreceptor signal that carl be mimicked by protein kinase C activation; this signal may be responsible for the convergenc e of the signaling mechanisms of these distinct seven-transmembrane an d tyrosine kinase receptors, mie suggest that translocation of G(i alp ha) to the nucleus induced by either thrombin or EGF may occur without subunit dissociation, Functional studies of the role of G(i) showed t hat pertussis toxin does riot block DNA synthesis ill Swiss 3T3 fibrob lasts induced by serum or thrombin, but that cell proliferation is ret arded to each, These results provide direct evidence for a novel mecha nism of GTP binding protein activation and for an essential role of G( i) in the induction of cell division by a variety of growth factor rec eptors, G(i) can carry out this role in control of cellular proliferat ion through its translocation to the nucleus of mitotic cells.