p73beta is regulated by protein kinase Cdelta catalytic fragment generated in the apoptotic response to DNA damage.
Protein kinase C (PKC) delta is cleaved by caspase-3 to a kinase-active catalytic fragment (PKCdeltaCF) in the apoptotic response of cells to DNA damage. Expression of PKCdeltaCF contributes to the induction of apoptosis by mechanisms that are presently unknown. Here we demonstrate that PKCdeltaCF associates with p73beta, a structural and functional homologue of the p53 tumor suppressor. The results show that PKCdeltaCF phosphorylates the p73beta transactivation and DNA-binding domains. One PKCdeltaCF-phosphorylation site has been mapped to Ser-289 in the p73beta DNA-binding domain. PKCdeltaCF-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation. By contrast, PKCdeltaCF-induced activation of p73beta is attenuated by mutating Ser-289 to Ala (S289A). The results also demonstrate that PKCdeltaCF stimulates p73beta-mediated apoptosis and that this response is attenuated with the p73beta(S289A) mutant. These findings demonstrate that cleavage of PKCdelta to PKCdeltaCF induces apoptosis by a mechanism in part dependent on PKCdeltaCF-mediated phosphorylation of the p73beta Ser-289 site.
Ren
Jian
J
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Datta
Rakesh
R
Shioya
Hisashi
H
Li
Yongqing
Y
Oki
Eiji
E
Biedermann
Verena
V
Bharti
Ajit
A
Kufe
Donald
D
D017209:Apoptosis; D020134:Catalytic Domain; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000737:chemistry / Q000502:physiology*; D051745:Protein Kinase C-delta; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D007527:Isoenzymes; D009687:Nuclear Proteins; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta