Constitutive expression of B-myb can bypass p53-induced Waf1/Cip1-mediated G1 arrest.
Overexpression of wild-type p53 protein has been shown to induce arrest in the G1 stage of the cell cycle and to transactivate expression of the gene that encodes the 21-kDa Waf1/Cip1 protein, a potent inhibitor of cyclin-dependent kinase activity. p53-dependent G1 arrest is accompanied by decreased expression of the B-myb gene, a relative of the c-myb cellular oncogene. In this study we show that B-myb expression is required for cells to progress from G1 into S phase and that high levels of ectopic B-myb expression uncoupled from cell cycle regulation rescues cells from p53-induced G1 arrest even in the presence of Waf1/Cip1 transactivation and inhibition of cyclin E/Cdk2 kinase activity. Cotransfection experiments with p53 expression plasmids and expression plasmids encoding in-frame deletion mutations in B-myb coding sequences indicate that the DNA-binding domain of the B-Myb protein is required for this activity. These results provide evidence of a bypass of p53-induced Waf1/Cip1-mediated cell cycle regulatory pathways by a member of the myb oncogene family.
Lin
D
D
Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19170.
Fiscella
M
M
O'Connor
P M
PM
Jackman
J
J
Chen
M
M
Luo
L L
LL
Sala
A
A
Travali
S
S
Appella
E
E
Mercer
W E
WE
D001483:Base Sequence; D015152:Blotting, Northern; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D016193:G1 Phase; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009857:Oncogenes; D012516:Osteosarcoma; D010957:Plasmids; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C064352:MYBL2 protein, human; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53