title: Inhibition of TFII-I-dependent cell cycle regulation by p53.
abstract: 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.
authors.affiliation: Program in Immunology, Sackler School of Graduate Biomedical Sciences, Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Zana P
authors.initials: ZP
authors.lastname: Desgranges
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.forename: Maria B
authors.initials: MB
authors.lastname: Lazebnik
authors.forename: Todd
authors.initials: T
authors.lastname: Ashworth
authors.forename: Caleb
authors.initials: C
authors.lastname: Lee
authors.forename: Richard C
authors.initials: RC
authors.lastname: Pestell
authors.forename: Naomi
authors.initials: N
authors.lastname: Rosenberg
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.forename: Ananda L
authors.initials: AL
authors.lastname: Roy
mesh_terms: 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
chemical_list: 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