Article

Counteracting MDM2-induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells.

Department of Experimental Oncology, Molecular Oncogenesis Laboratory, National Cancer Institute Regina Elena, Rome, Italy.
FEBS letters (impact factor: 3.54). 10/2010; 584(19):4253-8. DOI:10.1016/j.febslet.2010.09.018 pp.4253-8
Source: PubMed

ABSTRACT Homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, its tumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomal degradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptotic function. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53 ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylation and p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivatives are potential molecules to target the MDM2-induced HIPK2/p53 inhibition.

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Keywords

crucial regulator
 
DNA damage
 
HIPK2
 
HIPK2-induced p53Ser46 phosphorylation
 
Homeodomain-interacting protein kinase-2
 
MDM2 targets HIPK2
 
MDM2-induced HIPK2/p53 inhibition
 
phosphorylating serine 46
 
protein degradation impairing p53-apoptotic function
 
targets p53
 
wild-type p53
 
zinc antagonised MDM2-induced HIPK2 degradation
 
zinc inhibitory effect