Assistant Professor, Department of Molecular Pharmacology
We are interested in elucidating signaling pathways controlling cell growth and proliferation. Uncontrolled cell proliferation results in several disorders, most notably cancer. We focus on the role mammalian target of rapamycin (mTOR) pathway in cancer. Our goal is to identify downstream effectors of the mTOR pathway that confer proliferative advantage to cancer cells.
Our recent work indicates there exists a close interaction between the mTOR pathway and Estrogen Receptor (ER) signaling, specifically in the context of ER-positive breast cancer. Clinically, up to 60% of breast cancers are ER-positive, indicative of estrogen dependence for cancer cell growth. ER-positive cancers can be targeted therapeutically by endocrine therapy, however resistance often develops. Recently, we determined that the mTOR effector S6K1 directly phosphorylates ERα, leading to ligand-independent activation. Moreover, expression of the gene encoding for S6K1 is estrogenically regulated, creating a positive feed-forward signaling loop. This signaling relationship may be one of the underlying molecular mechanisms of escape from endocrine therapy, and could be targeted to create effective combination therapeutic strategies.
Alayev A, Sun Y, Snyder RB, Berger SM, Yu JJ, Holz MK. Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells. Cell Cycle. 2014; 13(3):371-82.
Alayev A. and Holz MK. mTOR Signaling for Biological Control and Cancer. J. Cell. Physiol., 2013;228: 1658–1664.
Holz, MK. The role of S6K1 in ER-positive breast cancer. Cell Cycle, 2012; 11(17):3159-65.
Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-González S, Holz MK. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene,2012; 31(49):5073–5080.
Yamnik RL and Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Lett. 2010; 584(1):124-8.
Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009; 284(10):6361-9.
Holz MK and Blenis J. (2008) Ribosomal protein S6 kinase beta-1 target assessment review. Targeted Proteins Database, Current Biodata. doi:10.2970/tpdb.2008.212.
Holz MK and Blenis J. (2008) Ribosomal protein S6 kinase beta-2 target assessment review. Targeted Proteins Database, Current Biodata. doi:10.2970/tpdb.2008.161.
Holz MK and Blenis J. (2008) Eukaryotic translation initiation factor 4E-binding protein 1 target assessment review. Targeted Proteins Database, Current Biodata. doi:10.2970/tpdb.2008.208.
Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007;282(19):14056-64.
Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123(4):569-80.
Holz MK and Blenis J.Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase.J Biol Chem. 2005;280(28):26089-93.
More Information About Dr. Marina Holz
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New York, NY 10016