To reveal mechanisms involved in the early stages of melanoma development, Dr. Ronai has elucidated the mammalian response to UV-irradiation, being the major etiological agent in melanoma development. Through the characterization of a novel UV-response element (URE) he has identified a cyclic AMP response element-binding protein (CREB) in B16 mouse melanoma cells and an activating transcription factor 2 (ATF-2) in human melanoma cells. Expression of a dominant negative CREB or of dominant negative ATF-2 (ATF2dn in human melanoma cells (MeWo) resulted in poor resistance to irradiation, and diminished expression of high molecular weight melanoma-associated antigen. It is the working hypothesis that changes in a particular subset of UV-related transcription factors can override genomic alterations which dictate characteristic phenotypes of human melanoma. While present studies provide direct support for this hypothesis, future studies are aimed at delineating the mechanism(s) by which selective changes in the transcription factor ATF2 can alter phenotypes of melanoma cells. For that Dr. Ronai proposes to: 1. Identify proteins that form heterodimers with ATF-2 in order to mediate its activities in MeWo-AFT2dn melanoma cells; 2. Identify critical domains which confer AFT2dn activities; 3. Test the ability of ATF2dn to modulate melanoma growth and metastatic potential in vivo. 4. Identify mechanisms involved in ATF2dn ability to alter melanoma phenotypes. Through the use of UV-irradiated melanocytes, melanoma and MeWo-AFT2dn, he will determine the changes in genes known to be regulated by ATF2 and expected to participate in the UV-response. Cellular components that are found to be modulated in MeWo-AFT2dn cells will be further evaluated for their inherent ability to alter radiation resistance and metastatic potential.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA051995-07
Application #
2429727
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1991-01-01
Project End
2001-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Feng, Yongmei; Lau, Eric; Scortegagna, Marzia et al. (2013) Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11. Pigment Cell Melanoma Res 26:136-42
Gandin, Valentina; Gutierrez, Gustavo J; Brill, Laurence M et al. (2013) Degradation of newly synthesized polypeptides by ribosome-associated RACK1/c-Jun N-terminal kinase/eukaryotic elongation factor 1A2 complex. Mol Cell Biol 33:2510-26
Lau, Eric; Ronai, Ze'ev A (2012) ATF2 - at the crossroad of nuclear and cytosolic functions. J Cell Sci 125:2815-24
Lau, Eric; Kluger, Harriet; Varsano, Tal et al. (2012) PKC? promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell 148:543-55
Yanagiya, Akiko; Suyama, Eigo; Adachi, Hironori et al. (2012) Translational homeostasis via the mRNA cap-binding protein, eIF4E. Mol Cell 46:847-58
Lopez-Bergami, Pablo; Kim, Hyungsoo; Dewing, Antimone et al. (2010) c-Jun regulates phosphoinositide-dependent kinase 1 transcription: implication for Akt and protein kinase C activities and melanoma tumorigenesis. J Biol Chem 285:903-13
Barile, Elisa; De, Surya K; Carlson, Coby B et al. (2010) Design, synthesis, and structure-activity relationships of 3-ethynyl-1H-indazoles as inhibitors of the phosphatidylinositol 3-kinase signaling pathway. J Med Chem 53:8368-75
Lopez-Bergami, Pablo; Lau, Eric; Ronai, Ze'ev (2010) Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10:65-76
Refaeli, Yosef; Bhoumik, Anindita; Roop, Dennis R et al. (2009) Melanoma-initiating cells: a compass needed. EMBO Rep 10:965-72
Lopez-Bergami, Pablo; Ronai, Ze'ev (2008) Requirements for PKC-augmented JNK activation by MKK4/7. Int J Biochem Cell Biol 40:1055-64

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