RNA antisense abrogation of MAT1 induces G(1) phase arrest and triggers apoptosis in aortic smooth muscle cells

The human MAT1 gene (menage a trois I) is an assembly factor and a targetin g subunit of cyclin-dependent kinase (CDK)-activating kinase. The novel mec hanisms by which MAT1 forms an active CDH-activating kinase and determines substrate specificity of CDK7-cyclin H are involved in the cell cycle, DNA repair, and transcription. Hyperplasia of vascular smooth muscle cells (SMC ) is a fundamental pathologic feature of luminal narrowing in vascular occl usive diseases, and nothing is yet known regarding the cell cycle phase spe cificity of the MAT1 gene in its involvement in SMC proliferation. To inves tigate such novel regulatory pathways, MAT1 expression was abrogated by ret rovirus-mediated gene transfer of antisense MAT1 RNA in cultured rat aortic SMCs. We show that abrogation of MAT1 expression retards SMC proliferation and inhibits cell activation from a nonproliferative state. Furthermore, w e have demonstrated that these effects are due to G(1) phase arrest and apo ptotic cell death. Our studies indicate a link between cell cycle control a nd apoptosis and reveal a potential mechanism for coupling the regulation o f MAT1 with G(1) exit and prevention of apoptosis.