Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1)

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Abstract
The tumor suppressor p53 is regulated in part by binding to cellular proteins. We used p53 as bait in the yeast two-hybrid system and isolated homeodomain-interacting protein kinase 1 (HIPK1) as a p53-binding protein. Deletion analysis showed that amino acids 100–370 of p53 and amino acids 885-1093 of HIPK1 were sufficient for HIPK1–p53 interaction. HIPK1 was capable of autophosphorylation and specific serine phosphorylation of p53. TheHIPK1gene was highly expressed in human breast cancer cell lines and oncogenically transformed mouse embryonic fibroblasts.HIPK1was localized to human chromosome band 1p13, a site frequently altered in cancers. Gene-targetedHIPK1−/− mice were grossly normal but oncogenically transformedHIPK1−/− mouse embryonic fibroblasts exhibited reduced transcription ofMdm2and were more susceptible than transformedHIPK1+/+ cells to apoptosis induced by DNA damage. Carcinogen-treatedHIPK1−/− mice developed fewer and smaller skin tumors thanHIPK1+/+ mice. HIPK1 may thus play a role in tumorigenesis, perhaps by means of the regulation of p53 and/or Mdm2.