Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1).
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. The HIPK1 gene was highly expressed in human breast cancer cell lines and oncogenically transformed mouse embryonic fibroblasts. HIPK1 was localized to human chromosome band 1p13, a site frequently altered in cancers. Gene-targeted HIPK1-/- mice were grossly normal but oncogenically transformed HIPK1 -/- mouse embryonic fibroblasts exhibited reduced transcription of Mdm2 and were more susceptible than transformed HIPK1+/+ cells to apoptosis induced by DNA damage. Carcinogen-treated HIPK1 -/- mice developed fewer and smaller skin tumors than HIPK1+/+ mice. HIPK1 may thus play a role in tumorigenesis, perhaps by means of the regulation of p53 and/or Mdm2.
Kondo
Seiji
S
Advanced Medical Discovery Institute, and Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2C1.
Lu
Ying
Y
Debbas
Michael
M
Lin
Athena W
AW
Sarosi
Ildiko
I
Itie
Annick
A
Wakeham
Andrew
A
Tuan
JoAnn
J
Saris
Chris
C
Elliott
Gary
G
Ma
Weili
W
Benchimol
Samuel
S
Lowe
Scott W
SW
Mak
Tak Wah
TW
Thukral
Sushil K
SK
D000818:Animals; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C115113:Hipk1 protein, mouse; D017346:Protein Serine-Threonine Kinases