Analysis of the regulatory mechanisms that control DLG tumour suppressor expression

CAVATORTA, ANA L.; CHOUHY, DIEGO; ADRIANA ANGELICA GIRI; GARDIOL, DANIELA

Pinamar

Congreso; XLI Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2005

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

High risk HPVs play a causal role in the development of cervical cancer. HPV E6 oncoproteins target h-Dlg (Dlg) for ubiquitinmediated proteolysis. Dlg oncosuppressor is associated with cellcell interactions, cell polarity and regulation of proliferation. We analysed, by immunohistochemistry, the level of expression and localization of Dlg in HPV-related lesions of different grades of severity. 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. Different hypothesis can be proposed to explain the different Dlg expression patterns  observed in the various pathologies investigated: a) 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. b) The mechanisms controlling Dlg expression at the transcriptional level are still poorly understood. In order to understand the basic Dlg gene transcriptional regulation we proposed the cloning of Dlg gene promoter region, its functional analysis and the study of sequences with probable transcriptional regulatory functions.