L'oncoproteina E7 di Human Papillomavirus interagisce con la proteina cellulare GSTP1 e ne modula la funzionalità
Author(s)
Mattarocci, Stefano
Date Issued
February 20, 2009
Type
Doctoral Thesis
Abstract
Human Papillomavirus (HPV)-16 is a paradigm for “high-risk” HPVs, which are the
causative agents of virtually all cervical carcinomas. The viral oncoprotein E7, along with
E6, is the key factor for the transformation of the infected cell. By direct protein-protein
interaction, we identified glutathione S-transferase P1-1 (GSTP1) as a novel cellular target
of the E7 oncoprotein from HPV-16. After a molecular mapping of the HPV-16 E7 amino
acids involved, we generated a three-dimensional molecular model of the interaction
between the oncoprotein and GSTP1, which allowed us to engineer a HPV-16 E7 mutant
molecule strongly impaired in its ability to bind GSTP1. Exogenous HPV-16 E7 expression
in HaCaT human immortalized keratinocytes induced dramatic changes in the intracellular
redox equilibrium. Nevertheless, in this context, HPV-16 E7 appeared to protect GSTP1
from oxidative inactivation, increasing the amount of reduced GSTP1, which, as a
monomer, inhibits pro-apoptotic JNK phosphorylation, enhancing the survival ability of the
cell. Using the GSTP1-deficient MCF-7 cancer cell line as well as siRNA interference
targeting GSTP1 in HaCaT keratinocytes expressing the wild-type or the mutant
oncoprotein, we underscored a pivotal role for GSTP1 in the pro-survival program elicited
by HPV-16 E7, providing further evidence of the transforming abilities of this oncoprotein.
This study sets the groundwork for devising unique molecular tools to interfere with the
interaction between HPV-16 E7 and GSTP1 and to minimize the survival of HPV-16 E7-
expressing human cancer cells.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
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