By analogy to Mdm2, exactly where very low ubiquitination results in nuclear export and polyubiquitination effects in degradation, it will be tempting to propose that mono ubiquitination of p53 by E6 E6AP may perhaps also signal p53 for nuclear export, though poly ubiquitination may well stimulate degradation during the nucleus as well as cytoplasm. The capability of c Abl to block degradation and nuclear export, suggests that it could control both levels of p53 ubiquitination. Even so, this probability is still to be tested. It is vital to note that p53 protected by c Abl is transcriptionally lively. In non infected cells co expression of c Abl with E6 restores the ability of p53 to induce p53 target promoters. Likewise, in HPV infected cells c Abl was recognized to trigger p53 action 94 . Additionally, ectopic expression of c Abl in HPV infected cells induces efficient apoptosis, which could be blocked by down regulation of p53 by using siRNA for p53 T.G. and Y.H unpublished information . These findings render c Abl a potential candidate to the advancement of medicines aimed at restoration of p53 apoptotic activity in HPV induced cancer, this kind of as cervical carcinoma.
The mechanism by which c Abl protects p53 from E6 E6AP is just not clear nonetheless. It will be intriguing, however, that c Abl protects p53 from the two the regular cellular degradation machinery, likewise as machinery employed from the virus, pathways which are mutually exclusive 105 . This could possibly suggest that c Abl may secure p53 by targeting a vital step tgf inhibitors required by Mdm2 in addition to the E6 E6AP complicated. Since the kinase action of c Abl is needed for its safety from Mdm2, it can be tempting to propose that E6 E6AP or other part from the degradation pathway is targeted by c Abl for phosphorylation. Other potential mechanisms cannot be ruled out at this stage. C Abl seems to be abundantly expressed in HPV contaminated cells T.G. and Y.H unpublished success . This raises the question why endogenous c Abl is insufficient for triggering p53 by DNA harm to efficiently kill HPV contaminated cells. It can be probable that HPV viral protein s deregulate c Abl, one example is by abrogating the kinase activity or by interfering with all the sub cellular localization of c Abl.
The acquiring that c Abl can set off p53 in HPV contaminated cells supports this notion, yet this can be still to be explored. Oncogenic c Abl and p53 Constitutive activation of c Abl kinase action will be oncogenic. This takes place when the N terminal portion of c Abl is replaced with fragments of genes, such as bcr, tel or the viral gag, producing the fusion specific Src inhibitor tyrosine kinases Bcr Abl, Tel Abl, and v Abl, respectively reviewed in 112,113 . In these fusion proteins, numerous portions in the N terminal inhibitory region of c Abl are eliminated, resulting in a constitutive tyrosine kinase action within the fusion proteins reviewed in 109 .