Ation of Akt by PTEN. e Akt activity is negatively regulated
PTEN specically catalyzes the dephosphorylation of three phosphate from the inositol ring in phosphatidylinositol (3,four,5)triphosphate (PIP3 ) resulting inside the With HIV: Web-site employees reported testing volunteers for HIV, giving counseling biphosphate product phosphatidyl (4,5)-biphosphate (PIP2 ). PTEN is regulated by the protooncogene ubiquitin ligase NEDD4-1 (neural precursor cell expressed, developmentally downregulated 4) that promotes PTEN for proteasomal degradation . In many human cancer samples exactly where the genetic background of PTEN was regular, but its protein level was low, NEDD4-1 was extremely expressed . Upon TCR/CD28 stimulation of T cells, PTEN undergoes inactivation by NEDD4-1 . e association amongst PTEN and NEDD4 could be impeded by the E3 ubiquitin ligase Cbl-b (Casitas-B-lineage lymphoma protein-b) . Cblb-/- T cells show elevated Akt activity, which was abrogated by simultaneous deciency in NEDD4 . PTEN can also be negatively regulated by the anti-apoptotic XIAP (X-linked inhibitor of apoptosis) that promotes PTEN for polyubiquitination and proteosomal degradation . Induction of apoptosis in B-CLL by arsenic trioxide was shown to lead to activation of c-Jun-NH2 terminal kinase (JNK), inactivation of AKT and NFB, XIAP downregulation, and PTEN upregulation . Two other E3 ligases downregulating PTEN incorporate WWP2 (WW-domain containing protein2 or AIP-2, atrophin-1-interacting protein two) , and CHIP (chaperone-associated E3 ligase C terminus of Hsc70interacting protein) . Lately, PTEN was shown to become upregulated by dexamethasone . 126.96.36.199. Regulation of PTEN Stability by MicroRNAs. PTEN expression may also be repressed by a range of microRNAs such as the miR-1792 cluster [247, 248], miR-106b25 , miR-21 , miR-26a [253, 315], miR-29b , miR-214 [317, 318], miR-216a and miR-217 , miR-212 [.Ation of Akt by PTEN. e Akt activity is negatively regulated by PTEN (phosphatase and tensin title= SART.S23506 homolog deleted on chromosome ten), title= fpsyg.2015.01413 a tumor suppressor gene which is suppressed, mutated, or deleted at higher frequency in a big quantity of cancers . PTEN mutations or deletions are frequent in T-ALL and PTEN deletions are related with much less favorable outcome in T-ALL [104, 300]. e PTEN status of the cell affects drug sensitivity. As an example, therapy of T-ALL with gamma secretase inhibitor (GSI) was only efficient when the cells expressed functional PTEN . A single mechanism by which Notch confers GC resistance is by way of PTEN inhibition major to Akt activation. PTEN specically catalyzes the dephosphorylation of 3 phosphate from the inositol ring in phosphatidylinositol (3,4,5)triphosphate (PIP3 ) resulting inside the biphosphate product phosphatidyl (4,five)-biphosphate (PIP2 ). PIP3 is a second messenger generated by PI3K that binds to the pleckstrin homology (PH) domain of Akt, which enables its phosphorylation and activation by the 3-phosphoinositide-dependent protein kinase 1 (PDK1) . 2.4.2.two. Regulation of PTEN Stability by Phosphorylation and Ubiquitination. Taken into account the important part of PTEN in figuring out drug sensitivity, mechanisms9 regulating PTEN activity and stability have powerful impact on the drug response. PTEN is regulated by a number of mechanisms . Besides gene mutation and deletion, decreased PTEN expression has been attributed to epigenetic events for example promoter methylation [302, 303]. At the posttranslational level, phosphorylation and ubiquitination decrease PTEN protein levels, while oxidation and acetylation reduce PTEN activity .