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Seminar Notes from December 14, 2006

December 14, 2006

Dr. Henske from Fox Chase Cancer Center and Dr. Avruch: Estrogen, mTOR, and metastatsis

Amy’s introduction and thanks; update on LAM patients, encouraging researchers to make progress; goals of seminar series and format.
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Dr. Henske

Topics:
2 biochemical mechanisms related to LAM
2 unpublished models
            Xenograph model
            Yeast model

1. What is LAM?  Normal lung, alveolar cells become hyperplastic in LAM -- can come on quickly; effects only women.

 

1. A cell lacking TSC1 or TSC2 (no known source) leads to AMLs.  Cell has ability to spread to lung in estrogen dependent manner.  Believe LAM cells are metastatic.  Could come from kidney, or some third source.  Explored two main pathways:
1. B-Raf and C-raf kinase regulation.
2. Estrogen mediated pathways

1. Tuberin activates B-raf and p42/44 mapk, which is counterintuitive.  Tuberin null have less phosphorylation--   Consistent with work years prior. 

 

1. Rapamycin insensitive, shows independent pathway, not mTOR dependent.

1. Does Rheb also inhibit C-Raf?  [C-raf seems to have common targets as B-raf.]  Answer, yes.  C-raf has little activity in absence of serum stimulation (different from B-raf).  Rheb clearly inhibits C-raf and B-raf in rapamycin resistant manner.

 

1. Rheb also inhibits association of C-raf and B-raf.  The association between C-Raf and B-Raf is critical for activity of both kinases. 

1. Rheb inhibits B-raf /Ras binding, with or without serum.  Control and Rheb siRNA (Rheb inhibits interaction)

 

1. Rheb binds to and directly inhibits B-Raf, forming a complex which inhibits both B-raf and C-raf (perhaps Ras in direct competitive manner as well, but not sure).  What role, if any, in TSC pathogenesis?

1. Estrogen in cells that have TSC2.  expose mcf-7 breast cancer cells to estrogen, phosphorylation p70s6k in 15 min.  blocked by rapamycin and wartmannin.

 

1. Classical estrogen receptor model--  Estrogen rapidly activates mTOR
2. Using NDP kinase to label GTP, resolve with TLC.  Rhep-GDP falls after 5, 15 minutes of estrogen.

1. Some of signaling involving rapid phosphorylation of TSC2.  How does this affect growth of breast cancer cells?  Does down regulation of Rheb have effect on cell proliferation?

 

1. Estrogen induced growth over 72 hrs completely removed by Rheb siRNA.  Accompanied by change in G1 fraction of cells

1. Tuberin and Rheb regulation of cell growth.  Mapk inhibitors block growth with rapamycin and wartmannin. 

 

1. Question for LAM is what happens in cells lacking TSC2 --> xenograph model.

Talk notes uploaded to website edited at the discretion of Dr. Henske. Complete presentation has not been provided.

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Dr. Avruch’s presentation and discussion notes will be uploaded to this site shortly.