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Experimental models of transformatio...

Boehm, Jesse Samuel.

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Experimental models of transformation as platforms for oncogene discovery.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Experimental models of transformation as platforms for oncogene discovery./
作者:	Boehm, Jesse Samuel.
面頁冊數:	119 p.
附註:	Adviser: William C. Hahn.
Contained By:	Dissertation Abstracts International68-02B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3251254

Experimental models of transformation as platforms for oncogene discovery.
Boehm, Jesse Samuel.

Experimental models of transformation as platforms for oncogene discovery. - 119 p.

Adviser: William C. Hahn.

Thesis (Ph.D.)--Harvard University, 2007.

The successful development of rational anti-neoplastic therapeutics relies both upon an improved understanding of the genetic pathways that conspire to program cellular transformation and the identification of specific transforming molecules within these pathways. My dissertation focuses on the construction of increasingly relevant in vitro model systems of human cell transformation and the characterization of their utility for oncogene discovery.Subjects--Topical Terms:

1017686
Biology, Cell.

Experimental models of transformation as platforms for oncogene discovery.
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245 1 0 $a Experimental models of transformation as platforms for oncogene discovery.
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520 $a The successful development of rational anti-neoplastic therapeutics relies both upon an improved understanding of the genetic pathways that conspire to program cellular transformation and the identification of specific transforming molecules within these pathways. My dissertation focuses on the construction of increasingly relevant in vitro model systems of human cell transformation and the characterization of their utility for oncogene discovery.
520 $a Murine embryo fibroblasts are readily transformed by the introduction of specific combinations of oncogenes; however, the expression of those same oncogenes in human cells fails to convert such cells to tumorigenicity. Using normal human and murine embryonic fibroblasts, I show that the transformation of human cells requires several additional alterations beyond those required to transform comparable murine cells. These genetic differences involve the pathways regulated by telomerase, as well as the RB and PTEN tumor suppressor proteins. These experiments permitted the development of transformed human fibroblasts with genetic alterations similar to those found associated with human cancers and defined specific differences in the susceptibility of human and murine fibroblasts to experimental transformation.
520 $a These in vitro model systems of human cell transformation were further leveraged in both candidate- and screening-based discovery efforts. I demonstrate that activation of the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways cooperate to replace H-RASV12 (RAS) in the transformation of human cells. Using a library of activated kinases, I identified several kinases that replace PI3K signaling and render cells tumorigenic. Whole genome structural analyses revealed that one of these kinases, IKBKE (IKKepsilon), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKepsilon expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKepsilon overexpression activates the nuclear factor kappa B (NF-kappaB) transcription factor, consistent with the observed activation of this pathway in many breast cancers. These observations implicate the NF-kappaB pathway as an essential downstream mediator of PI3K. Furthermore, they provide a framework for integrated genomic approaches in oncogene discovery and demonstrate the utility and relevance for cell-based models of human malignancy.
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