MAT1-modulated CAK activity regulates cell cycle G(1) exit.
The cyclin-dependent kinase (CDK)-activating kinase (CAK) is involved in cell cycle control, transcription, and DNA repair (E. A. Nigg, Curr. Opin. Cell. Biol. 8:312-317, 1996). However, the mechanisms of how CAK is integrated into these signaling pathways remain unknown. We previously demonstrated that abrogation of MAT1 (ménage à trois 1), an assembly factor and targeting subunit of CAK, induces G(1) arrest (L. Wu, P. Chen, J. J. Hwang, L. W. Barsky, K. I. Weinberg, A. Jong, and V. A. Starnes, J. Biol. Chem. 274:5564-5572, 1999). This result led us to investigate how deregulation of CAK by MAT1 abrogation affects the cell cycle G(1) exit, a process that is regulated most closely by phosphorylation of retinoblastoma tumor suppressor protein (pRb). Using mammalian cellular models that undergo G(1) arrest evoked by antisense MAT1 abrogation, we found that deregulation of CAK inhibits pRb phosphorylation and cyclin E expression, CAK phosphorylation of pRb is MAT1 dose dependent but cyclin D1/CDK4 independent, and MAT1 interacts with pRb. These results suggest that CAK is involved in the regulation of cell cycle G(1) exit while MAT1-modulated CAK formation and CAK phosphorylation of pRb may determine the cell cycle specificity of CAK in G(1) progression.
Wu
L
L
Department of Pathology, Childrens Hospital Los Angeles Research Institute, Los Angeles, California 90027, USA. lingtaow@hsc.usc.edu
Chen
P
P
Shum
C H
CH
Chen
C
C
Barsky
L W
LW
Weinberg
K I
KI
Jong
A
A
Triche
T J
TJ
D002455:Cell Division; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D013379:Substrate Specificity; D014161:Transduction, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D016213:Cyclins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase