The identity of these proteins is at present becoming investigated lengthy phrase target is always to set up the profile of PTENs subcellular localization in relation to your activation states in the PI3K signaling cascade to improve the molecular diagnosis, prognosis, prediction, and person ized targeted therapy for GBM. Together, these findings show that c Met induced glioblastoma malignancy is strongly amplified by PTEN loss. These selleck inhibitor findings indicate that experi mental therapeutic approaches that combine inhibition of SF/HGF,c Met with reconstitution of PTEN could bring about enhanced anti tumor effects. This kind of experimental therapeutic approaches are now staying tested in our laboratory. This study was supported by National Institutes of Health grant R01 NS045209. CB 18. NUCLEAR PTEN Like a Probable THERAPEUTIC MOLECULE IN GBM Juinn Lin Liu,one Ta Jen Liu,1 Kenneth D. Aldape,2 Zhenyu Mao,1 Tiffany A.
LaFortune,one and W. K. Alfred Yung1, 1Brain Tumor Center, Department of Neuro Oncology, and 2Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA The phosphoinositide 3 kinase /AKT/mTOR/p70S6K signaling cascade is prevalently activated in GBMs as being a outcome of deletion/mutation of the PTEN tumor suppressor gene or activation/amplification selleckchem of PI3K signaling components. PTEN plays differential development regulatory roles from the cytoplasm versus the nucleus. Within the cytoplasm, it has intrinsic lipid phosphatase exercise that specifically antagonizes the PI3K pathway. While in the nucleus, PTEN displays Akt independent growth suppressing routines. Previously, we demonstrated that PTENs cell cycle dependent nuclear export is triggered by the PI3K cascade, specifically p70S6K, during G1/S transition.
The exported PTEN isn’t only released from its nuclear growth suppressing activities but also can dephosphorylate cytoplasmic PIP3 to prevent the constitutive activation of Akt mediated signaling pathways. This scenario exemplifies a reciprocal regulation amongst PI3K and PTEN. To determine the downstream target genes exclusively modulated by nuclear PTEN, we developed an ecdysone inducible

expression system in U251 HF cells. An Affymetrix oligonucleotide microarray analysis identified several nuclear PTEN specific genes that may contribute to cell development suppres sion, including topoisomerase IIA, cdk1, cyclin A2, and cyclin B1. We also verified their expression at the protein level. In congruence with the find ings in other advanced human tumors, our immunohistochemical analysis results showed that PTEN was predominantly expressed while in the cytoplasm if it was not deleted in GBM tumors. Conversely, S6 is constitutively phos phorylated regardless of PTEN status. This is certainly further supported by our observation of preferential cytoplasmic localization of PTEN in several GBM cell lines, including LN229. We next evaluated the potential of using nuclear PTEN as a therapeutic molecule in GBMs expressing cytoplasmic wild type PTEN. Our preliminary data showed that nuclear PTEN, but not wild type PTEN, suppressed the anchorage independent development of LN229 cells.