1. TSC2 and Tuberous Sclerosis Complex Disease www.xray2000.f9.co.uk/ibase3/rain/album20.html Laura Koontz Biology 169

2. TSC2 TSC2 encodes the protein tuberin Tuberin was found to be a GTPase Activating Protein (GAP) specific to Rheb, a Ras-like protein Mutations in TSC2 cause inappropriate activation of Rheb and downstream effectors

3. Lodish et al. Fig. 20-22 GAPs help GTPases (like Ras and Rheb) hydrolyze GTP

4. TSC2 (Tuberin) blocks Rheb signaling in the absence of ligand Manning, B.D., et. al. Rheb fills a GAP between TSC and TOR. 2003. Trends in Biochemical Science. 28: 573 – 576.

5. In the presence of growth factor, TSC2 (Tuberin) is inhibited Manning, B.D., et. al. Rheb fills a GAP between TSC and TOR. 2003. Trends in Biochemical Science. 28: 573 – 576. Downstream effectors that turn on protein synthesis

6. TSC2 functions to regulate cell growth Tapon, N., et. al. 2001. The Drosophila Tuberous Sclerosis Complex Gene Homologs Restrict Cell Growth and Cell Proliferation. Cell 10:345 – 355.

7. TSC2 +/- mice develop bilateral tumors; a good model for human TS Arrows indicate bilateral renal tumors developing concurrently (from a 7 month old female mouse) Kobayashi, T., et. al. 1999. Renal Carcinogenesis, Hepatic Hemangiomatosis, and Embryonic Lethality Caused by a Germ-Line TSC2 Mutation in Mice. Cancer Research 59: 1206 – 1211.

8. TSC2 is a tumor suppressor TSC2 down-regulates the production of protein synthesis machinery in the absence of ligand. TSC2 -/- mutant cells have an increased cell size, but do not divide. Mutations in TSC2 are inherited in an autosomally dominant manner, comparable to RB inheritance.

9. How is TSC2 related to cancer? Tuberous sclerosis derives its name from the tuber-like growths associated with it. These growths, called hamartomas, are benign tumors that can effect many different organs in the body: Brain Kidneys www.schoolscience.co.uk/content/5/biology/mrc/15/page4.html www.xray2000.f9.co.uk/ibase3/rain/album20.html http://myweb.lsbu.ac.uk/~dirt/museum/unk-chest.html Skin Heart Lungs