Background: The TSC1/TSC2 complex integrates multiple cues to regulate the pro-growth kinase, mammalian target of rapamycin (mTOR). Inactivating mutations in TSC1/TSC2 promote uncontrolled mTOR activity and drive tuberous sclerosis tumor formation. Studies indicate that TSC mutant flies with excessive mTOR activity exhibit increased levels of growth-inhibitory FOXO transcription factors (TFs), suggesting that the benign nature of tuberous sclerosis tumors results from an mTOR-dependent feedback pathway involving FOXO TFs. Importantly, the FOXO regulated stress-response protein, cyclin G2 (G2), is elevated upon treatment of cells with mTOR inhibitors and induction of endoplasmic reticulum (ER) stress. TSC1/TSC2 mutant cells are extremely sensitive to ER stress-invoking drugs.Hypothesis: As elevated G2 expression coincides with growth-arrest responses preceding apoptosis, and ectopic G2 inhibits proliferation, we hypothesize that G2 restricts tuberous sclerosis tumor growth and promotes apoptosis in the face of heightened ER stress. We seek to determine whether elevated G2 expression induced by mTOR inhibitors or ER stress contributes to growth-restriction of TSC-deficient tumors.Specific Aims: Using gene knock-down technology in normal wild-type and TSC-deficient cells, we will:(1) Assess the degree to which G2 contributes to growth arrest in rapamycin treated cells.(2) Determine whether G2 upregulation during ER stress modulates cell proliferation and viability. Impact: These studies will further our understanding of the role FOXO regulated genes play in the sensitivity of tuberous sclerosis tumors to mTOR inhibitors and ER stress-invoking therapeutics.
|Effective start/end date||4/15/09 → 7/14/11|
- Congressionally Directed Medical Research Programs: $112,500.00