title: The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage.
abstract: The non-receptor tyrosine kinase c-Abl is activated in response to DNA damage and induces p73-dependent apoptosis. Here, we investigated c-Abl regulation of the homeodomain-interacting protein kinase 2 (HIPK2), an important regulator of p53-dependent apoptosis. c-Abl phosphorylated HIPK2 at several sites, and phosphorylation by c-Abl protected HIPK2 from degradation mediated by the ubiquitin E3 ligase Siah-1. c-Abl and HIPK2 synergized in activating p53 on apoptotic promoters in a reporter assay, and c-Abl was required for endogenous HIPK2 accumulation and phosphorylation of p53 at Ser(46) in response to DNA damage by γ- and UV radiation. Accumulation of HIPK2 in nuclear speckles and association with promyelocytic leukemia protein (PML) in response to DNA damage were also dependent on c-Abl activity. At high cell density, the Hippo pathway inhibits DNA damage-induced c-Abl activation. Under this condition, DNA damage-induced HIPK2 accumulation, phosphorylation of p53 at Ser(46), and apoptosis were attenuated. These data demonstrate a new mechanism for the induction of DNA damage-induced apoptosis by c-Abl and illustrate network interactions between serine/threonine and tyrosine kinases that dictate cell fate.
authors.affiliation: From the Department of Molecular Genetics and.
authors.forename: Nina
authors.initials: N
authors.lastname: Reuven
authors.affiliation: From the Department of Molecular Genetics and.
authors.forename: Julia
authors.initials: J
authors.lastname: Adler
authors.affiliation: the Biological Services Unit, Weizmann Institute of Science, Rehovot 76100, Israel and.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Porat
authors.affiliation: the Cellular Senescence Group, Cell and Tumor Biology Program, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Polonio-Vallon
authors.affiliation: the Cellular Senescence Group, Cell and Tumor Biology Program, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
authors.affiliation: From the Department of Molecular Genetics and yosef.shaul@weizmann.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shaul
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D019281:Dimerization; D004789:Enzyme Activation / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases
keywords: ABL tyrosine kinase; DNA damage response; Hippo pathway; high cell density; homeodomain-interacting protein kinase 2 (HIPK2); p53; serine/threonine protein kinase; tyrosine kinase and serine/threonine kinase crosstalk