hDLG HPV E6-mediated degradation and carcinogenesis

CAVATORTA, ANA LAURA; CHOUHY, DIEGO; AGUIRRE, ROXANA; NOCITO, ANA LIA; GIRI, ADRIANA A.; GARDIOL, DANIELA

Iguazu, Misiones

Congreso; XL Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2004

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

High risk HPVs play a causal role in the development of cervical cancer. HPV E6 oncoproteins target h-Dlg (Dlg) for ubiquitin-mediated proteolysis. Dlg oncosuppressor is associated with cell-cell interactions, cell polarity and regulation of proliferation. Dlg was expressed in cervical intraepithelial lesions (SIL), but it was absent in samples derived from invasive carcinoma. Although the presence of high risk HPV was detected in some SIL specimens, Dlg levels were high. E6 phosphorylation by protein kinase A (PKA) reduces its capacity for binding to Dlg and thereby reduces E6-stimulation of Dlg degradation. We analyzed PKA activity in cervical samples by immunohistochemistry. We demonstrated variations in PKA activity during the development of cervical tumors that could be altering E6 phosphorylation status, and this should explain the differences in Dlg expression observed in intraepithelial or invasive HPV-associated lesions. Taking into account Dlg functions in the cell, its down-regulation mediated by E6 may contribute to transformation and to the occurrence of some of the characteristics of the HPV-transformed cells, such as changes in cell morphology, loss of polarity and high migration ability. We obtained a cancer HPV-associated cell line over-expressing Dlg, that is being used as a model for studying the incumbency of Dlg degradation in such cell properties.