Thus, increased level of Cdk5 activator may facilitate Cdk5 mediated phosphorylation of overex pressed p53, which causes cell growth inhibition. The decreased level of p35 protein in HTet43GFP cells does not cause cell growth inhibition because of unavailability of its substrate. Though, Cdk5 plays an important role in activating overexpressed p53, as such it is not involved http://www.selleckchem.com/products/Bortezomib.html in Inhibitors,Modulators,Libraries the pro liferation of parental HeLa cells per se in spite of the fact that E6 expression leads to increase in Cdk5 protein expression. p53 executes its apoptotic function through intrinsic or extrinsic pathways. To further confirm the pathway involved, we investigated Bax, an important transcriptional target of p53 involved in promoting intrinsic mitochon drial apoptosis.

Bax translocates to mitochondrial outer membrane causing MOMP and releases cytochrome C into cytosol. Inhibitors,Modulators,Libraries Cells lacking Bax or those overexpressing Bcl 2 are profoundly resistant to a broad range of apoptotic stimuli, including chemotherapeutic drugs treat ment and serum starvation. In HPV positive cancers Bcl 2 overexpression and Bax degradation by E6 facilitates cancer progression. Here, we demonstrate that upre gulated Bax translocates to mitochondria upon PP2A inhi bition in p53 overexpressing cells which is dependent on Cdk5 activity. Thus, only phosphorylated p53 triggers Bax transcription to increase its levels and cause apoptosis. In addition, the cell cycle arrest caused by inhibition of PP2A in p53 overexpressing cells may be dependent on tran scriptional upregulation of p21 gene.

Collectively these Inhibitors,Modulators,Libraries data also provide Inhibitors,Modulators,Libraries evidence for reactivation of E6 disrupted p21 and Bax pathways in HPV positive cells. Finally, we propose that Cdk5 interacts with p53 and phosphorylates Ser20 and Ser46 residues. Phosphoryla tion restores the ability of overexpressed p53 to specifi cally bind on p21 and bax promoters. These findings provide novel insight into the regulation of p53 transactivation functions and propose PP2A to be a key player in modulating p53 functionality. The phosphory lated status of specific residues may be involved in pro moter selection and this proposition needs further investigations. Also, this is the first report which pro vides mechanism for functional activation of p53, and details the essential modifications necessary for non genotoxically overexpressed p53 to be able to execute its tumor suppressor functions in HPV positive cells. More over, activation of overexpressed p53 without targeting viral Inhibitors,Modulators,Libraries oncogenes may have implication next in the treatment of virus infected carcinomas. The efforts towards the newer approaches to target p53 pathway and usefulness of reactivation of p53 pathways in treatment of cancers are encouraging.