[Download] "Unraveling the Signaling Network in Human Cell Transformation" by Rocky Cipriano # eBook PDF Kindle ePub Free

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eBook details

• Title: Unraveling the Signaling Network in Human Cell Transformation
• Author : Rocky Cipriano
• Release Date : January 18, 2013
• Genre: Medical,Books,Professional & Technical,Science & Nature,
• Pages : * pages
• Size : 18202 KB

Description

The use of cellular transformation models has aided our understanding of tumorigenesis. The continued refinement of these cellular models is critical to expanding our understanding of the signaling pathways dysregulated in cancer and linking specific genetic alterations with the therapeutic efficiencies of new treatment options. In studies described here ablation of p73, or PTEN, or overexpression of BCL-2 resulted in a transformed phenotype which retained wild-type p53. Using this model of cellular transformation has allowed the dissection of genetic alterations that confer a sensitive or resistant phenotype to Nutlin-3, an HDM2 antagonist currently in clinical trials. Our results suggest that treating tumors harboring inactive PTEN, p73, or with elevated BCL-2 expression with Nutlin-3 could re-engage p53 activity and induce apoptosis, arguing that therapies aimed at reactivating p53 could prove efficient in tumors harboring these genetic alterations. Such studies are critical in light of findings demonstrating HDMX overexpression protects cells from Nutlin-3 toxicity. As cell culture models of human cell transformation evolve, a more detailed analysis of the pathways commonly altered during cancer development can begin to be defined. Using normal human mammary epithelial cells (HMECs) obtained from reduction mammoplasties, we established a cellular model of the basal or triple negative subtype of breast cancer. This progressive model of breastcancer initiation uncovered a novel TGF-beta mediated suppressive barrier engaged by dysregulated oncogenic signaling. Unlike fibroblasts, we report here that HMECs undergo a TGF-beta-mediated OIS in response to oncogenic RAS, which does not require p53, p16, ATM or CHK2. Finally, my studies led to the discovery and characterization of a novel oncogene, FAM83B, identified by combining a phenotypic based forward genetic screen with a HMEC transformation model. FAM83B is a previously uncharacterized protein, identified here as a driver of HMEC transformation that functions by hyperactivating the MAPK and mTOR signaling cascades. We further demonstrate that FAM83B is a member of an eight protein family which contains a conserved N-terminal DUF 1669, that is necessary and sufficient for a transformed phenotype. The results presented here have (1) linked transforming events with the therapeutic efficiency of Nutlin-3, (2) identified a novel growth arrest pathway responsible for suppressing breast cancer initiation and (3) identified a novel oncogene family which may result in the development of novel therapeutics.

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