Your SlideShare is downloading. ×
mTOR: growth regulator involved in disease
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

mTOR: growth regulator involved in disease

3,085

Published on

Dr. Sabatini's powerpoint presentation from the October 26, 2006 meeting for the LAM/TSC Boston Research SEminar

Dr. Sabatini's powerpoint presentation from the October 26, 2006 meeting for the LAM/TSC Boston Research SEminar

Published in: Technology, Economy & Finance
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
3,085
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
0
Comments
0
Likes
2
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1.  
  • 2. mTOR: growth regulator involved in disease
  • 3. mTOR pathway and disease Incorporates contributions from labs of Blenis, Thomas, Hafen, Cantley, Pan, White, Kwiatkowski, Hunter, Edgar, and many others. TSC/LAM
  • 4. mTOR pathway and disease TSC/LAM
  • 5. mTOR pathway and disease: the important inhibitory loop TSC/LAM
  • 6. rapamycin Rapamycin and its uses Immunosuppressant blocks acute rejection by inhibiting T-cell mediated immunity Anti-cancer CCI-779, RAD001, AP23573 derivatives in clinical trials (PTEN null cancers, TSC tumors? LAM?) Prevents restenosis after angioplasty
  • 7. mTOR exists in at least two distinct protein complexes mTORC1 mTORC2
  • 8. Key role of Akt phosphorylation in PI3K/PTEN/Akt pathway Active Akt Inactive Akt mTORC2 ? Other proposed kinases PKC, PDK1, DNA-PK, ILK, ATM
  • 9.
    • Characterization of mice missing mTORC components mTOR, raptor, mLST8/GbL, or rictor
    • Open questions around the mTOR pathway and LAM/TSC
  • 10. Mice null for mTORC1 and mTORC2 components David Guertin Deanna Stevens All components are encoded by essential genes
  • 11. wild- type Raptor -/- mTOR -/- G  L -/- (mLST8)
  • 12. rictor G  L/mLST8 G  L G  L
  • 13. Vessel defects in G  L/mLST8-null yolk sacs and embryos mTOR, rictor, raptor, and G  L/mLST8 KOs fall into two classes, likely reflecting absence of mTORC1 or mTORC2 function
  • 14. Biochemical analysis of E10.5 rictor & G  L/mLST8 null embryos Rictor G  L/mLST8
  • 15. mTORC1 pathway activity in G  L null MEFs Loss of G  L/mLST8 has no apparent effect on any mTORC1 pathway assay Why?
  • 16. G  L/mLST8 is necessary for mTORC2 but not mTORC1 integrity G  L: G  L: G  L:
  • 17. Signaling by hemi-phosphorylated Akt mTORC2 is necessary only for signaling to FOXO Why does hemi-phosphorylated Akt signal to some effectors but not others? What does G  L/mLST8 do for mTORC1?
  • 18. mTOR functions in two distinct complexes and pathways FOXO
  • 19. Open questions around targeting mTOR pathway
    • Is rheb the disease-relevant effector of TSC1/2?
    • If so, is mTOR the disease-relevant effector of TSC/rheb?
    • Is it best to target mTOR or a downstream effector like S6K1?
    • Will long-term removal by rapamycin of the inhibitory signal from S6K1 to the PI3K pathway produce unacceptable toxicities?
    • Will effect of long term rapamycin on mTORC2 have clinical implications
    • Will TSC and LAM differ in above questions?
  • 20. Is rheb the disease-relevant effector of TSC1/2? Is mTOR the disease-relevant effector of TSC/rheb? PRO Much work in Drosophila and mammalian tissue culture What is the key evidence needed to be able to say yes with confidence? CON Other known effects of TSC2 loss. Other known targets of rheb. Incapacity of rapamycin to reverse all effects of TSC1/TSC2 loss. How can we rule out or in other potential effectors?
  • 21. Tavazoie et al. Nat Neuro (2005) 8: 1727
  • 22. Crino et al. NEJM (2006) 355: 1345
  • 23. Is it best to target mTOR or a downstream effector like S6K1? No evidence either way. How can this be tested?
  • 24. Will long-term removal by rapamycin of the inhibitory signal from S6K1 to the PI3K pathway produce unacceptable toxicities? Will TSC and LAM cells differ in above question? Will effect of long term rapamycin on mTORC2 have clinical implications?
  • 25.  
  • 26. Anne Carpenter Jacob Chudnovsky Xana Frias David Guertin Peggy Hsu Ray Jones Nada Kalaany Tony Kang Mike Lamprecht Kathleen Ottina Funding Whitehead Institute, NIH (NIAID, NCI, GM), Keck Foundation, Pew Charitable Trust, Rita Allen Foundation The RNAi Consortium (TRC) Jason Moffat Adam Papallo Tim Peterson Jan Reiling Yasemin Sancak Dos Sarbassov Shomit Sengupta Joon-Ho Sheen Deanna Stevens Carson Thoreen

×