AKT2 Oncogene and Human Oncogenesis

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DESCRIPTION (provided by applicant): We recently cloned the AKT2 promoter and an AKT2-associated protein, NGB, which possesses GTPase and GTP-binding activities. The AKT2 promoter contains a number of transcription factor-binding sites and is induced by v-src and MyoD. Ectopic expression of NGB in tumor cells exhibits tumor suppressor activity. AKT2 interacts with, phosphorylates NGB and abrogates NGB-inhibited cell proliferation. Moreover, mutations of NGB were detected in 5 of 27 gliomas examined but not in matched normal DNA. In addition, we have demonstrated that AKT2 interacts with and phosphorylates tuberous sclerosis (TSC) 2 tumor suppressor as well as down-regulates TSC1 and TSC2 proteins, cDNA microarray analyses with RNA prepared from doxycycline-inducible constitutively active (myr-AKT2) and dominant negative AKT2- transfected cells revealed that of 12,000 genes examined, 68 genes were changed more than 5 folds. The gene that showed the largest increase in myr-AKT2 cells is the hHbl-deltaN gene. We have detected frequent upregulation of this gene in human cancer cell lines and primary tumors. Moreover, ectopic expression of the hHbl-deltaN induces cell survival, growth and transformation and activates AKT2 pathway, indicating that hHbl- deltaN plays an important role in AKT2 function. Based on these data, we hypothesize that the AKT2 is regulated by oncogenic transcription factors and that AKT2 and its associated proteins, NGB and TSC2, as well as its transcriptionally regulated gene(s) play a pivotal role in the control of cell proliferation and transformation. The broad, long-term objective of this project is to elucidate the normal cellular function of the AKT2 protein and determine the importance of perturbations of the AKT2 pathway in human oncogenesis. The specific aims are: (1) Identify the DNA response elements and transcription factors that regulate AKT2. (2) Define the role of the AKT2-associated protein NGB in AKT2 signaling. (3) Examine the effects of AKT2 phosphorylation of TSC2 on TSC1/TSC2 function. (4) Characterize the AKT2-transcriptionally regulated gene hHbl-AN identified by cDNA microarray.