Homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic functionby phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, itstumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomaldegradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptoticfunction. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylationand p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivativesare potential molecules to target the MDM2-induced HIPK2/p53 inhibition.
Counteracting MDM2-induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells
D'Orazi, Gabriella
2010-01-01
Abstract
Homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic functionby phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, itstumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomaldegradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptoticfunction. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylationand p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivativesare potential molecules to target the MDM2-induced HIPK2/p53 inhibition.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
