How cells switch HIPK2 on and off.
Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging regulator of cell growth and apoptosis in various cell types, tissues and organisms. Previous work indicates that HIPK2 is a potential tumour suppressor and DNA damage-responsive kinase, which phosphorylation-dependently activates the apoptotic programme by engaging diverse downstream targets, including tumour suppressor p53 and the anti-apoptotic transcriptional corepressor C-terminal binding protein. The regulation of HIPK2, however, remained largely obscure. Recent studies show that HIPK2 activity is mainly controlled at the post-transcriptional level through targeted proteolysis. Caspase-dependent processing triggers HIPK2 hyperactivation, whereas the ubiquitin-proteasome system (UPS) keeps HIPK2 in check by targeting it for degradation. Both HIPK2 hyperactivation and HIPK2 degradation are under the control of transcription factor p53. Negative regulation of HIPK2 by the UPS is abolished in response to DNA damage, which facilitates HIPK2 stabilization and activation. Here we discuss these findings in the context of DNA damage signalling and tumour suppression.
Sombroek
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Cellular Senescence Group, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Hofmann
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D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
D002352:Carrier Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020169:Caspases