Date

August 2007

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular and Medical Genetics

Institution

Oregon Health & Science University

Abstract

C-Myc is a powerful oncogenic transcription factor. Originally discovered through its homology to the avian expressed myelocytomatosis virus transforming gene, v-myc (Vennstrom et al. 1982), c-myc has been intensely studied for the past 20 years due to both the requirement of c-myc for normal development (Davis et al. 1993) and the high prevalence of elevated c-Myc expression in a wide array of human cancers (Nesbit et al. 1999). The potent oncogenic capacity of c-Myc has been demonstrated by increased proliferation, neoplastic transformation, and inhibition of differentiation in cultured cells with sustained overexpression of c-Myc (Evan et al. 1992). Moreover, expression of c-Myc in mice with inducible c-myc transgenes develop neoplastic pre-malignant and malignant phenotypes that often spontaneously regress when c-myc expression is shutoff (Felsher and Bishop 1999; Pelengaris et al. 1999). Part of a non-redundant family of proteins that includes N-Myc, L-Myc, S-Myc, and BMyc, c-Myc or cellular-Myc is the ubiquitously expressed form of the Myc family that is believed to regulate the expression of ~15% of all genes (Patel et al. 2004). C-Myc has been characterized extensively as a transcription factor since it was shown to contain several domains common to other transcription factors that include a transactivation domain in the N-terminal region as well a basic region, leucine zipper and helix-loop-helix motifs in the C-terminal region that allow for sequence specific DNA binding and heterodimerization with Max, see Figure 1.1 (Landschultz et al. 1998; Davis et al. 1990; Kato et al. 1990; Luscher and Eisenman 1990). The transcription factor, c-Myc has been shown to regulate the expression of numerous genes involved in cellular proliferation, growth, differentiation, angiogenesis and apoptosis (Cole 1986; Luscher and Eisenman 1990; Prendergast 1999). More specifically, several studies have demonstrated the c-Myc drives cellular proliferation and growth by increasing the expression of genes that positively regulate the cell cycle and ribosomal biogenesis and inhibiting the expression of genes that negatively regulate cell cycle progression (Zeller et al. 2003; White 2005). Furthermore, c-Myc expression inhibits differentiation (Coppola and Cole 1986; Miner and Wold 1991) and c-Myc plays an important role in promoting angiogenesis and vascularogenesis in tumors (Baudino et al. 2002). Moreover, c-Myc has been shown to be one of four critical factors for the self-renewal of stem cells (Coppola and Cole 1986; Takahashi and Yamanaka 2006). Altogether, these findings demonstrate potential mechanisms through which c-Myc can act as potent oncoprotein. However, c-Myc expression is also shown to induce apoptosis in "normal" cells (Pelengaris et al. 2002; Nilsson and Cleveland 2003), thereby confounding the previous findings supporting the oncogenic function of c-Myc. More recent studies have now shown that the induction of apoptosis by overexpression of c-Myc is likely a "normal" response to a high cellular oncogenic load. Apoptosis under these conditions of elevated c-Myc expression results from the activation of p53 through ARF's ability to prevent p53 degradation as well as c-Myc mediated release of cytochrome c though up-regulation of Fas (Kavurma and Khachigian 2003; Dai et al. 2006). Interestingly, these pathways for inducing apoptosis are often compromised early in tumorgenesis, thereby allowing the oncogenic functions of c-Myc to drive tumorgenesis. Altogether, these findings highlight the importance of maintaining "normal" c-Myc expression.

Identifier

doi:10.6083/M4W9574K

School

School of Medicine

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.