Ellis R. Levin
M.D.-Jefferson Medical School, 1975
Fellowship-Endocrinology, UCLA, 1981
Long Beach VA Medical Center/UC-Irvine
5901 E 7th St
Long Beach, CA 90822
Office: (562) 826-5748
My lab focuses on the plasma membrane estrogen receptor (ER) and its effects on the biology of estrogen action. This includes both in-vitro and in-vivo models. Our work always stems from a clinically important observation in humans that is mechanistically not understood. The focus currently is on 1) estrogen action to promote breast cancer development,2) blood vessel development (angiogenesis) and function, and the 3) anti-hypertrophy effects of estrogen on the cardiomyocyte. As part of the studies, we are trying to understand the molecular structure /function aspects of the membrane estrogen receptor, that allows for signaling, and membrane localization. These studies involve mutagenesis or inhibition of endogenous receptors, and genetic mouse models (ER knockout).
Estrogen use after the menopause leads to increased risk of breast cancer. We have shown that this results from both increased proliferation of breast cancer cells and increased survival. In fact, tamoxifen, taxol or radiation treatment of breast cancer causes apoptosis, and we showed that estrogen prevents this. Both proliferation and survival effects of ER are importantly mediated through signaling to ERK MAP kinase via the membrane ER. This leads to detailed cell cycle events, and anti-apoptotic events that we have delineated, involving JNK signaling to Bcl-2 and Bcl-xl inactivation, and prevention of formation of the apoptosome. Important cell cyle events involving proliferation include estrogen-induced cyclins B and D1 proteins, and cdk4 and cdc2 activation. Signaling from the membrane ER requires cross-activation of the membrane EGF receptor, and we have published many of the details of this cross-talk between G-protein coupled ER and the tyrosine kinase EGFR. Our most recent work has defined a new interaction between the tumor suppressor BRCA1 and membrane ER signaling, resulting in breast cancer proliferation. Mutation of BRCA1, as in women who develop breast cancer, results in the loss of restraint of membrane ER and growth factor signaling through ERK, predisposing to breast cancer development.
In blood vessels, membrane ER stimulates EC migration and survival, and angiogenesis. This occurs through activation of p38 MAP kinase-MAPKAP-2-heat shock protein 27 induction. We are defining exactly the role of hsp27 in this process. We also recently found that estrogen protects cardiomyocytes against the development of hypertrophy, which fits with human studies showing protection by estrogen against the development of heart failure. The mechanisms and genes involved are being delineated using DNA array, si RNA and other approaches, in-vitro and in-vivo.
Razandi, M., Alton, G., Pedram, A., Ghonshani S., Webb D., and Levin, ER. Identification of a structural determinant for the membrane localization of ERa. Mol Cell Biol 23: 1633-1646, 2003.
Razandi M., Pedram, A, Rosen, E., and Levin, ER. BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer. Mol Cell Biol 24:5900-5913, 2004.
Razandi,M., Pedram, A., Merchenthaler, I.,Greene, GL., and Levin, ER. Plasma membrane estrogen receptors exist and function as dimers. Mol Endocrinol 18:2854-2865, 2004.
Guo, X., Razandi, M., Pedram, A., Kassab, G., and Levin, ER. Estrogen induces vascular wall dilation: Mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta. J Biol Chem, 280:19704-19710, 2005.
Levin, ER. Integration of the extra-nuclear and nuclear actions of estrogen.Mol Endocrinol 19(8): 1951-1959, 2005.
Evinger, AE II, and Levin ER. Requirements for estrogen receptor a membrane localization and function. Steroids 70:361-363, 2005.
Pedram, A., Razandi, R., Aitkenhead, M., and Levin, ER. 2005 Estrogen inhibits cardiomyocyte hypertrophy in-vitro: Antagonism of calcineurin-related hypertrophy through Induction of MCIP1. J Biol Chem 280:26339-26348, 2005.
Pietras, R., Levin, ER., and Szego, CM. Estrogen receptors and cell signaling (short correspondence letter). Science 310:51-53, 2005.
Guo,X., Lu, X., Ren, H., Levin, ER., and Kassab GS. Estrogen modulates the mechanical homeostasis of mouse arterial vessels through nitric oxide. Am J Physiol Heart Circ Physiol 290(5):H1788-1797,2006.
Kim JK., Pedram A., Razandi M., and Levin, ER. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 isoforms. J Biol Chem 281:6760-6767,2006
Pedram, A., Razandi, M., Wallace, DC., and Levin, ER. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 17:2125-2137,2006.
Pedram, A., Razandi, M., and Levin, ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol 20(9):1996-2009,2006.
Kim, J., and Levin, ER. Estrogen signaling in the cardiovascular system. Nuclear Receptor Signaling 4:e013-e027,2006