Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation.
Members of the Wnt family of signal transducers regulate cellular differentiation/reorganization and cellular proliferation. However, few pro-proliferative targets of Wnt have been identified. We now show that cyclin D1, a critical mediator of cell cycle progression, is a downstream target of Wnt-dependent signaling. NIH-3T3 cell lines engineered to overexpress Wnt1 displayed reduced glycogen synthase kinase-3beta activity. Wnt1-dependent glycogen synthase kinase-3beta inhibition corresponded with decreased cyclin D1 proteolysis and, thus, hyperaccumulation of active cyclin D1.CDK4 (cyclin-dependent kinase 4) kinase. However, in the absence of serum-derived growth factors, Wnt-1 was not sufficient to drive cyclin D1 accumulation or S-phase entry. In contrast, cells engineered to co-express Wnt1 and activated MEK1 accumulated high levels of cyclin D1 and entered the DNA synthetic phase in the absence of serum-derived growth factors, a characteristic of neoplastic transformation. The ability of a dominant-negative cyclin D1 mutant, D1-T156A, to inhibit Wnt1/MEK1-dependent S-phase entry suggests that cyclin D1 is a critical downstream target for Wnt1- and MEK1-dependent cellular proliferation.
Rimerman
R A
RA
Eppley Institute for Research in Cancer and Allied Diseases, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Gellert-Randleman
A
A
Diehl
J A
JA
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006868:Hydrolysis; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016196:S Phase; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D019938:Cyclin D1; D038341:Glycogen Synthase Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases