Flowchart: Preparation: PTEN
 


                 

Text Box: P13K


       

Text Box: Igfbp-2


Text Box: Igf-II


                                            

                                                

                                                                                      

                   

Text Box: PTENBreast cancer

Brain tumor

Prostate cancer

 


                                         

 


                                                    

Text Box: AKT
 


                                      

Free Radic Biol Med. 2007 Apr 15;42(8):1178-92. Epub 2007 Jan 12.Click here to read  Links

Phosphorylation of the survival kinase Akt by superoxide is dependent on an ascorbate-reversible oxidation of PTEN.

P     Lim S, Clement MV.

Yong Loo Lin School of Medicine, Department of Biochemistry, National University of Singapore, Singapore 119260, Singapore.

In this report, we demonstrate that in serum-deprived mouse embryonic fibroblasts an increase in intracellular level of superoxide through pharmacological inhibition of the Cu/ZnSOD protein or the down-regulation of its expression using specific siRNA mimics growth factor-induced phosphorylation of Akt. Using the PI3K inhibitor LY294002 and PTEN knockout mouse embryonic fibroblasts, we show that phosphorylation of Akt by superoxide requires the production of PIP3 and that the target for the induction of Akt phosphorylation by O(2)(-) is the phosphatase PTEN. Interestingly, the inhibition of PTEN involves an O(2)(-)-mediated oxidation of the phosphatase rather than regulation of its phosphorylation or decreased protein expression. Moreover, using differential reduction of oxidized protein by DTT and ascorbate, O(2)(-)-dependent oxidation of PTEN is shown to be due to S-nitrosylation of the protein. Finally, exposure of serum-deprived mouse embryonic fibroblasts to fetal bovine serum leads to a rapid and strong phosphorylation of Akt that is dependent on an ascorbate-reversible O(2)(-)-mediated oxidation of PTEN. These results support O(2)(-) as a physiologically relevant second messenger for Akt activation through S-nitrosylation of PTEN and offer a mechanistic explanation for the mitogenic and prosurvival activities of O(2)(-).

PMID: 17382199 [PubMed - in process]

Biochim Biophys Acta. 2007 Feb 20; [Epub ahead of print]Click here to read  Links

Phosphatidylinositol 3-kinase regulation of gastrin-releasing peptide-induced cell cycle progression in neuroblastoma cells.

P     Ishola TA, Kang J, Qiao J, Evers BM, Chung DH.

Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.

Gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BBS), is an autocrine growth factor for neuroblastoma; its receptor is up-regulated in undifferentiated neuroblastomas. Phosphatidylinositol 3-kinase (PI3K) is a critical cell survival pathway; it is negatively regulated by the PTEN tumor suppressor gene. We have recently found that poorly differentiated neuroblastomas express decreased PTEN protein levels. Moreover, overexpression of the GRP receptor, a member of the G-protein coupled receptor family, down-regulates PTEN expression, resulting in increased neuroblastoma cell growth. Therefore, we sought to determine whether GRP or BBS activates PI3K in neuroblastoma cells (BE(2)-C, LAN-1, SK-N-SH). GRP or BBS treatment rapidly increased phosphorylation of Akt and GSK-3beta in neuroblastoma cells. Inhibition of GRP receptor, with antagonist GRP-H2756 or siRNA, attenuated BBS-induced phosphorylation of Akt. LY294002, a PI3K inhibitor, also abrogated BBS-stimulated phospho-Akt as well as its cell cycle targets. GRP increased G1/S phase progression in SK-N-SH cells. BBS-mediated BrdU incorporation was blocked by LY294002. Our findings identify PI3K as an important signaling pathway for GRP-mediated neuroblastoma cell growth. A novel therapy targeted at GRP/GRP receptor may prove to be an effective treatment option to inhibit PI3K in neuroblastomas.

PMID: 17379415 [PubMed - as supplied by publisher

Proc Natl Acad Sci U S A. 2007 Mar 19; [Epub ahead of print]Click here to read  Links

Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer.

P     Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK, Sawyers CL.

Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90089; Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

PTEN is an important tumor-suppressor gene associated with many cancers. Through expression profiling of glioblastoma tissue samples and prostate cancer xenografts, we identified a molecular signature for loss of the PTEN tumor suppressor in glioblastoma and prostate tumors. The PTEN signature consists of a minimum of nine genes, several of which are involved in various pathways already implicated in tumor formation. Among these signature genes, the most significant was an increase in insulin growth factor-binding protein 2 (IGFBP-2) mRNA. Up-regulation of IGFBP-2 was confirmed at the protein level by Western blot analysis and validated in samples not included in the microarray analysis. The link between IGFBP-2 and PTEN was of particular interest because elevated serum IGFBP-2 levels have been reported in patients with prostate and brain tumors. To further investigate this link, we determined that IGFBP-2 expression is negatively regulated by PTEN and positively regulated by phosphatidylinositol 3-kinase (PI3K) and Akt activation. In addition, Akt-driven transformation is impaired in IGFBP2(-/-) mouse embryo fibroblasts, implicating a functional role for IGFBP-2 in PTEN signaling. Collectively, these studies establish that PTEN and IGFBP-2 expression are inversely correlated in human brain and prostate cancers and implicate serum IGFBP-2 levels as a potential serum biomarker of PTEN status and PI3K Akt pathway activation in cancer patients.

PMID: 17372210 [PubMed - as supplied by publisher]

: Oncogene. 2007 Mar 19; [Epub ahead of print]Click here to read  Links

IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells.

P     Perks CM, Vernon EG, Rosendahl AH, Tonge D, Holly JM.

1IGF & Metabolic Endocrinology Group, Department of Clinical Sciences at North Bristol, Southmead Hospital, University of Bristol, Bristol, UK.

The dual-function phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is the second most frequently mutated gene in human cancers. PTEN counteracts the functions of many growth factors, the most prevalent of which is insulin-like growth factor II (IGF-II). PTEN expression is stimulated by IGF-II forming a feedback loop. Investigating IGF-binding protein (IGFBP) modulation of IGF-II actions on MCF-7 breast cancer cells, we found that IGFBP-2 also regulates PTEN. The MCF-7 cells were not responsive to high doses of IGF-II due to induction of PTEN, which was not observed with an IGF-II-analog that does not bind to IGFBPs or in the presence of an inhibitor that prevents IGFs associating with IGFBPs. These cells predominantly produce IGFBP-2: blocking IGFBP-2 with a specific antibody, or preventing IGFBP-2 binding to integrins, restored the induction of PTEN and the cells were non-responsive to high doses of the IGF-II-analog. Our findings indicate that breast cancer cells do not respond to high doses of IGF-II due to induction of PTEN, but IGFBP-2, when free from IGF-II can suppress PTEN. Levels of IGFBP-2 are elevated frequently in human tumors: its ability to regulate PTEN could have important implications in relation to therapeutic strategies targeting growth factor pathways.Oncogene advance online publication, 19 March 2007; doi:10.1038/sj.onc.1210397.

PMID: 17369847 [PubMed - as supplied by publisher]