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PMID: 15870287 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Role of epidermal growth factor receptor signaling in RAS-driven melanoma.

Molecular and cellular biology ·Vol. 25 ·No. 10 ·2005-05-00 ·Pages 4176-88

Bardeesy N, Kim M, Xu J, Kim RS, Shen Q, Bosenberg MW, Wong WH, Chin L

Abstract

The identification of essential genetic elements in pathways governing the maintenance of fully established tumors is critical to the development of effective antioncologic agents. Previous studies revealed an essential role for H-RAS(V12G) in melanoma maintenance in an inducible transgenic model. Here, we sought to define the molecular basis for RAS-dependent tumor maintenance through determination of the H-RAS(V12G)-directed transcriptional program and subsequent functional validation of potential signaling surrogates. The extinction of H-RAS(V12G) expression in established tumors was associated with alterations in the expression of proliferative, antiapoptotic, and angiogenic genes, a profile consistent with the observed phenotype of tumor cell proliferative arrest and death and endothelial cell apoptosis during tumor regression. In particular, these melanomas displayed a prominent RAS-dependent regulation of the epidermal growth factor (EGF) family, leading to establishment of an EGF receptor signaling loop. Genetic complementation and interference studies demonstrated that this signaling loop is essential to H-RAS(V12G)-directed tumorigenesis. Thus, this inducible tumor model system permits the identification and validation of alternative points of therapeutic intervention without neutralization of the primary genetic lesion.

MeSH Terms
Animals Autocrine Communication Cell Line, Tumor Cell Transformation, Neoplastic/genetics,metabolism,pathology ErbB Receptors/metabolism Gene Expression Profiling Gene Expression Regulation, Neoplastic Melanocytes/metabolism,pathology Melanoma/genetics,metabolism,pathology Mice Mice, SCID Mice, Transgenic Mitogen-Activated Protein Kinases/metabolism Neoplasm Transplantation Oncogene Protein p21(ras)/genetics,metabolism RNA, Neoplasm/analysis,genetics Signal Transduction Transcription, Genetic/genetics raf Kinases/metabolism
Chemicals
RNA, Neoplasm ErbB Receptors raf Kinases Mitogen-Activated Protein Kinases Oncogene Protein p21(ras)
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Bardeesy Nabeel
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. nelbardeesy@partners.org
Kim Minjung
Xu Jin
Kim Ryung-Suk
Shen Qiong
Bosenberg Marcus W
Wong Wing H
Chin Lynda
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.10.4176-4188.2005
Email
nelbardeesy@partners.org
Published
2005-05-00
Pages
4176-88
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1087708
Subset
IM
Grants
NCI NIH HHS · U01 CA084313 · United States
NCI NIH HHS · P20 CA096470 · United States
NCI NIH HHS · P50 CA093683 · United States
NCI NIH HHS · R01 CA093947 · United States
NCI NIH HHS · CA89124 · United States
NCI NIH HHS · U01 CA84313 · United States
NCI NIH HHS · P50 CA93683 · United States
NCI NIH HHS · P20 CA96470 · United States
NCI NIH HHS · K08 CA089124 · United States
NCI NIH HHS · R01 CA93947 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.10.4176-4188.2005 PMC Full Text View journal details
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