Inhibition of TFII-I-dependent cell cycle regulation by p53.
The multifunctional transcription factor TFII-I is tyrosine phosphorylated in response to extracellular growth signals and transcriptionally activates growth-promoting genes. However, whether activation of TFII-I also directly affects the cell cycle profile is unknown. Here we show that under normal growth conditions, TFII-I is recruited to the cyclin D1 promoter and transcriptionally activates this gene. Most strikingly, upon cell cycle arrest resulting from genotoxic stress and p53 activation, TFII-I is ubiquitinated and targeted for proteasomal degradation in a p53- and ATM (ataxia telangiectasia mutated)-dependent manner. Consistent with a direct role of TFII-I in cell cycle regulation and cellular proliferation, stable and ectopic expression of wild-type TFII-I increases cyclin D1 levels, resulting in accelerated entry to and exit from S phase, and overcomes p53-mediated cell cycle arrest, despite radiation. We further show that the transcriptional regulation of cyclin D1 and cell cycle control by TFII-I are dependent on its tyrosine phosphorylation at positions 248 and 611, sites required for its growth signal-mediated transcriptional activity. Taken together, our data define TFII-I as a growth signal-dependent transcriptional activator that is critical for cell cycle control and proliferation and further reveal that genotoxic stress-induced degradation of TFII-I results in cell cycle arrest.
Desgranges
Zana P
ZP
Program in Immunology, Sackler School of Graduate Biomedical Sciences, Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Ahn
Jinwoo
J
Lazebnik
Maria B
MB
Ashworth
Todd
T
Lee
Caleb
C
Pestell
Richard C
RC
Rosenberg
Naomi
N
Prives
Carol
C
Roy
Ananda L
AL
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C104259:GTF2I protein, human; D019473:Transcription Factors, TFII; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex