Ruolo della chinasi pro-apoptotica Hipk2 nella risposta ai farmaci antineoplastici: fosforilazione e degradazione dell'oncogene DeltaNp63α
Author(s)
Lazzari, Chiara
Date Issued
March 16, 2010
Type
Doctoral Thesis
Abstract
HIPK2 is a nuclear serine/threonine kinase initially identified for its interaction with homeodomain factors. HIPK2 is involved in several cellular processes, such as transcriptional regulation, proliferation control, development, differentiation and DNA damage response, through the interaction with a still increasing number of proteins. In particular, several studies demonstrate that HIPK2 has a role in severe genotoxic damage-induced apoptosis, through selective phosphorylation of p53 at Ser46 . Since p53 is a relevant player in determining cell sensitivity to antineoplastic drugs, we asked whether its activator HIPK2 is also involved in this response. We found that HIPK2 protein is stabilized upon treatment with different drugs such as Adriamycin Etoposide or Bleomycin, and that HIPK2 depletion by RNAi strongly induces drug resistance. Interestingly, both p53-dependent and independent mechanisms are involved in this HIPK2-mediated drug response, as shown by the induction of drug-resistance promoted by HIPK2 depletion in p53-null cells.
DeltaNp63α is a member of the p53 family that acts as a trascriptional factor with dominant-negative effects towards p53. Upon DNA damage, DeltaNp63α is phosphorylated and undergoes proteasomal degradation. Since HIPK2 was shown to interact with each member of the p53 family, we asked whether the HIPK2/p63 interaction has a functional role in cell response to genotoxic stress. By overexpression, RNAi, and biochemical studies, we found that DeltaNp63α is a HIPK2 target. In particular, we show that HIPK2 specifically phosphorylates p63 at threonine 397 thus promoting DeltaNp63α proteasomal degradation in response to Adriamycin treatment.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
Subjects
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