TSC2 and Tuberous Sclerosis Complex Disease
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TSC2 and Tuberous Sclerosis Complex Disease
www.xray2000.f9.co.uk/ibase3/rain/album20.html
Laura Koontz
Biology 169
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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
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Lodish et al. Fig. 20-22
GAPs help GTPases (like Ras and Rheb) hydrolyze GTP
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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.
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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
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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.
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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.
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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.
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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