PTEN can also regulate the ac tivity of the serinethreonine kinase AKTPKB and can selleck catalog thus influence cell survival signaling. UV ex posure can trigger Inhibitors,Modulators,Libraries PTEN interaction with wild type melanocortin 1 receptor variants, which protects PTEN from WWP2 mediated degradation, leading to AKT inactivation in melanoma. There are multiple mechanisms for the regulation of PTEN, including tran scription, mRNA stability, microRNA targeting, translation and protein stability. PTEN is transcriptionally silenced by promoter methylation in gastric carcinoma. PTEN can also be post translationally regulated by acetylation, ubiquitylation, oxidation, phosphorylation, and subcel lular localization. Despite extensive characterization of PTEN mutations in human cancers and a relatively good understanding of the molecular roles of PTEN in the control of cellular processes, little is known about modes of PTEN regulation.

PTEN can be inhibited in cancer cells upon induction of the pro inflammatory cytokine IL 1B. Stimulation with IL 1B activates NF kappaB by phosphorylation and degradation of IB. This activation allows NF Inhibitors,Modulators,Libraries kappaB to translocate into the nucleus and transcriptionally acti vate target genes. NF kappaB is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation Inhibitors,Modulators,Libraries subunit p65. High levels of endogenous NF kappaB decreased the expression of PTEN, and PTEN expression could be res cued by specific inhibition of the NF kappaB pathway. These findings indicate that NF kappaB activation is neces sary and sufficient for the inhibition of PTEN expression.

Importantly, the mechanism underlying suppression of PTEN expression by NF kappaB was independent of p65 transcription function. These studies Inhibitors,Modulators,Libraries indicate that other molecules may be involved in the process of PTEN expression inhibition by NF kappaB. In this study, we described a novel signaling pathway in which miR 425 can negatively control PTEN activa tion in cells upon IL 1B induction. The IL 1B induced expression of miR 425 was regulated by NF kappaB. Selective inhibition of PTEN by siRNA or miR 425 can improve cell survival in response to IL 1B treatment. However, we cannot rule out the possibility that IL 1B could induce additional miRNAs that could directly or indirectly target PTEN.

We presume that there are other IL 1B induced miRNAs involved in regulating PTEN expression because overexpression of anti miR 425 could not completely block PTEN repression. In addition to miR Inhibitors,Modulators,Libraries 425, miR 21 and miR 32 have been shown to target PTEN and to modulate growth, migration, and invasion in cancers of the digestive system. Downregulation of PTEN by miR 21 and miR 32 signifi cantly enhanced the survival and proliferation of human cancer cells exposed to inflammation selleckbio stress, further supporting a critical role for PTEN in the mediation of apoptosis.