Signaling through receptor tyrosine kinases is known to initiate a number of cellular events, and when deregulated are associated with many different disease states including cancer. Phosphoinositide 3-kinase (P13K) has been shown to be a major signaling protein downstream of tyrosine kinase receptors, although its direct targets have remained elusive. Protein kinase B, or c-akt, is a proto-oncogene that is amplified in a number of human tumors, and is activated by growth factors in a P13K-dependent manner. P13K itself is also increased in copy number in ovarian cancers. The importance of this pathway in tumor formation is suspected to be due to increasing cell survival,presumably through phosphorylation of the protein BAD by PKB. Recently, we identified and characterized a novel protein kinase termed phosphoinositide-dependent kinase-1 (PDK-1), which mediates the activation of PKB by P13K. The products of P13K act on this pathway by both activating PDK-1, and priming PKB for phosphorylation by PDK-1. This research proposal seeks to further characterize the role of PDK-1 in this pathway, to determine whether its activity is modulated in a growth factor-dependent manner, to see if its activity is required for PKB activation under a set of different conditions, and to screen for additional substrates of this kinase (Aim 1).
The second aim will address whether intramolecular interactions play a role in suppressing the activity of PKB under non-stimulating conditions, and ask whether additional proteins are involved in PKB activation. Finally the activity of the P13K/PKB pathway will be analyzed in a number of different tumor cells to determine the proportion of tumors containing elevated activity. The effect on tumorigenesis of inhibiting this pathway will also be examined (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079548-02
Application #
6137685
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Spalholz, Barbara A
Project Start
1999-01-01
Project End
2002-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
2
Fiscal Year
2000
Total Cost
$210,747
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ermoian, Ralph P; Kaprealian, Tania; Lamborn, Kathleen R et al. (2009) Signal transduction molecules in gliomas of all grades. J Neurooncol 91:19-26
Chen, Jack S; Zhou, Linda J; Entin-Meer, Michal et al. (2008) Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7:841-50
Bilanges, Benoit; Stokoe, David (2005) Direct comparison of the specificity of gene silencing using antisense oligonucleotides and RNAi. Biochem J 388:573-83
O'Shea, Clodagh; Klupsch, Kristina; Choi, Serah et al. (2005) Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. EMBO J 24:1211-21
Brandts, Christian H; Bilanges, Benoit; Hare, Gregor et al. (2005) Phosphorylation-independent stabilization of p27kip1 by the phosphoinositide 3-kinase pathway in glioblastoma cells. J Biol Chem 280:2012-9
Nakamura, Jean L; Karlsson, Amelia; Arvold, Nils D et al. (2005) PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol 71:215-22
Schramm, R D; Paprocki, A M (2004) In vitro development and cell allocation following aggregation of split embryos with tetraploid or developmentally asynchronous blastomeres in rhesus monkeys. Cloning Stem Cells 6:302-14
Woodrow, Melissa A; Woods, Douglas; Cherwinski, Holly M et al. (2003) Ras-induced serine phosphorylation of the focal adhesion protein paxillin is mediated by the Raf-->MEK-->ERK pathway. Exp Cell Res 287:325-38
Ermoian, Ralph P; Furniss, Constance S; Lamborn, Kathleen R et al. (2002) Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res 8:1100-6
Shtivelman, Emma; Sussman, Joshua; Stokoe, David (2002) A role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle. Curr Biol 12:919-24

Showing the most recent 10 out of 14 publications