Protein kinase C-dependent phosphorylation regulates the cell cycle-inhibitory function of the p73 carboxy terminus transactivation domain.
The transcription factor p73, a member of the p53 family of proteins, is involved in the regulation of cell cycle progression and apoptosis. However, the regulatory mechanisms controlling the distinct roles for p73 in these two processes have remained unclear. Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. We also characterized a second transactivation domain in the carboxy terminus of p73 within amino acid residues 381 to 399. This carboxy terminus transactivation domain was found to preferentially regulate genes involved in cell cycle progression. Moreover, its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388. Our results suggest that this novel posttranslational modification within the p73 carboxy terminus transactivation domain is involved in the context-specific guidance of p73 toward the selective induction of cell cycle arrest.
Nyman
Ulrika
U
Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Vlachos
Pinelopi
P
Cascante
Anna
A
Hermanson
Ola
O
Zhivotovsky
Boris
B
Joseph
Bertrand
B
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D009928:Organ Specificity; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017405:Herpes Simplex Virus Protein Vmw65; D050505:Mutant Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011493:Protein Kinase C