Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP

Qinghong Zhang, Yasuhiro Yoshimatsu, Jeffrey Hildebrand, Steven M. Frisch, Richard Goodman

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalCell
Volume115
Issue number2
DOIs
StatePublished - Oct 17 2003

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Homeodomain Proteins
Co-Repressor Proteins
Protein Kinases
Down-Regulation
Apoptosis
Small Interfering RNA
Embryonic Structures
Fibroblasts
Gene Library
Phosphotransferases
Up-Regulation
Genes
Irradiation
Mutation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. / Zhang, Qinghong; Yoshimatsu, Yasuhiro; Hildebrand, Jeffrey; Frisch, Steven M.; Goodman, Richard.

In: Cell, Vol. 115, No. 2, 17.10.2003, p. 177-186.

Research output: Contribution to journalArticle

Zhang, Qinghong ; Yoshimatsu, Yasuhiro ; Hildebrand, Jeffrey ; Frisch, Steven M. ; Goodman, Richard. / Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. In: Cell. 2003 ; Vol. 115, No. 2. pp. 177-186.
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abstract = "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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