TY - JOUR
T1 - Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP
AU - Zhang, Qinghong
AU - Yoshimatsu, Yasuhiro
AU - Hildebrand, Jeffrey
AU - Frisch, Steven M.
AU - Goodman, Richard H.
N1 - Funding Information:
This work was supported by grants from the NIH. We thank Y. Kim for providing the HIPK2 cDNA; S. Hollenberg for the VP16-cDNA library; M. Thayer for the siRNA vector; W. Ludlam for siRNA constructs for CtBP; J. Notis for CtBP E and A domains; and M. Iordanov, H. Lu, Y. Liu, S. Impey, and G. Mandel for helpful comments.
PY - 2003/10/17
Y1 - 2003/10/17
N2 - Genetic knockout of the transcriptional corepressor CtBP in mouse embryo fibroblasts upregulates several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP. To identify pathways involved in this regulation, we screened a mouse embryo cDNA library with an E1A-CtBP complex and identified the homeodomain interacting protein kinase 2 (HIPK2), which had previously been linked to UV-directed apoptosis through its ability to phosphorylate p53. Expression of HIPK2 or exposure to UV irradiation reduced CtBP levels via a proteosome-mediated pathway. The UV effect was prevented by coexpression of kinase-inactive HIPK2 or reduction in HIPK2 levels via siRNA. Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2-directed CtBP clearance. Finally, reduction in CtBP levels, either by genetic knockout or siRNA, promoted apoptosis in p53-deficient cells. These findings provide a pathway for UV-induced apoptosis in cells lacking p53.
AB - Genetic knockout of the transcriptional corepressor CtBP in mouse embryo fibroblasts upregulates several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP. To identify pathways involved in this regulation, we screened a mouse embryo cDNA library with an E1A-CtBP complex and identified the homeodomain interacting protein kinase 2 (HIPK2), which had previously been linked to UV-directed apoptosis through its ability to phosphorylate p53. Expression of HIPK2 or exposure to UV irradiation reduced CtBP levels via a proteosome-mediated pathway. The UV effect was prevented by coexpression of kinase-inactive HIPK2 or reduction in HIPK2 levels via siRNA. Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2-directed CtBP clearance. Finally, reduction in CtBP levels, either by genetic knockout or siRNA, promoted apoptosis in p53-deficient cells. These findings provide a pathway for UV-induced apoptosis in cells lacking p53.
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U2 - 10.1016/S0092-8674(03)00802-X
DO - 10.1016/S0092-8674(03)00802-X
M3 - Article
C2 - 14567915
AN - SCOPUS:0142258245
SN - 0092-8674
VL - 115
SP - 177
EP - 186
JO - Cell
JF - Cell
IS - 2
ER -