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Mutant -Subunit of the G Protein G12 Activates Proliferation and Inhibits Differentiation of 3T3-F442A Preadipocytes¹

Laboratoire de Biochimie de la Faculté de Médecine Paris-Ouest, INSERM CJF 94–02, Université René Descartes Paris V (D.D.-H., P.d.M., M.M., Y.G.), Paris; Hôpital de Poissy (D.D.-H., M.M., Y.G.), F78303 Poissy; and Hôpital R. Poincaré (P.d.M.), F92380 Garches, France

Address all correspondence and requests for reprints to: Dr. Philippe de Mazancourt, Laboratoire de Biochimie et Biologie Moléculaire, Hôpital R. Poincaré, F92380 Garches, France.

We studied the G protein -subunit G12 in various tissues and cell lines. Significant amounts of G12 were detected by immunoblots in liver, chromaffin cells, RINm5F cells, 3T3-F442A cells, and preadipocytes, but not in adipocytes, sperm, kidney, NB2A cells, or brain. To study the role of G12 in adipose tissue differentiation, the preadipocyte cell line 3T3-F442A was transfected with wild-type G12 or a constitutively activated mutant of G12. Stable expression of the activated mutant of G12 stimulated cell growth and inhibited preadipocyte differentiation. In contrast, wild-type G12 overexpression inhibited preadipocyte differentiation, without any effect on cell proliferation. The role of G12 on the Raf/MEK/mitogen-activating protein kinase (MAPK) cascade was studied. In confluent preadipocytes, expression of the activated mutant of G12 induced an increase in B-Raf expression, but no change in MAPK activity. Differentiation was associated with a decrease in MAPK activity in control 3T3-F442A cells. Wild-type G12 overexpression prevented the decrease in MAPK activity and induced MEK1, but not B-Raf, expression. Moreover, the activated mutant of G12 induced an increase in MAPK activity and in the expression of both MEK1 and B-Raf. These data indicate that the activated mutant of G12 stimulates the proliferation of 3T3-F442A preadipocytes, possibly through an increase in B-Raf expression, independently of the MEK/MAPK pathway, but prevents differentiation, probably through an increase in MEK1 expression and MAPK activity.

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