title: Heat shock modulates the subcellular localization, stability, and activity of HIPK2.
abstract: The homeodomain-interacting protein kinase-2 (HIPK2) is a highly conserved serine/threonine kinase and is involved in transcriptional regulation. HIPK2 is a highly unstable protein, and is kept at a low level under normal physiological conditions. However, exposure of cells to physiological stress - such as hypoxia, oxidative stress, or UV damage - is known to stabilize HIPK2, leading to the HIPK2-dependent activation of p53 and the cell death pathway. Therefore HIPK2 is also known as a stress kinase and as a stress-activated pro-apoptotic factor. We demonstrate here that exposure of cells to heat shock results in the stabilization of HIPK2 and the stabilization is mediated via K63-linked ubiquitination. Intriguingly, a sub-lethal heat shock (42 °C, 1 h) results in the cytoplasmic localization of HIPK2, while a lethal heat shock (45 °C, 1 h) results in its nuclear localization. Cells exposed to the lethal heat shock showed significantly higher levels of the p53 activity than those exposed to the sub-lethal thermal stress, suggesting that both the level and the nuclear localization are essential for the pro-apoptotic activity of HIPK2 and that the lethal heat shock could retain the HIPK2 in the nucleus to promote the cell death. Taken together our study underscores the importance of HIPK2 in stress mediated cell death, and that the HIPK2 is a generic stress kinase that gets activated by diverse set of physiological stressors.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, India.
authors.forename: Mamta
authors.initials: M
authors.lastname: Upadhyay
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, India.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Bhadauriya
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, India. Electronic address: sganesh@iitk.ac.in.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D018869:Heat-Shock Response; D006358:Hot Temperature; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Cell death pathway; Heat-shock response; Stress kinase; Ubiquitination