A 'non-canonical' DNA-binding element mediates the response of the Fas-ligand promoter to c-Myc.
Cell number is regulated by maintaining a balance between cell proliferation and cell death through apoptosis. Key regulators of this balance include the oncogene product c-Myc, which promotes either entry into the cell cycle or apoptosis [1]. Although the mechanism of c-Myc-induced apoptosis remains unclear, it is susceptible to regulation by survival factors [2,3] and can proceed through the interaction of Fas ligand (FasL) with its receptor, Fas [4]. Activated T lymphocytes are eliminated by an apoptotic process known as activation-induced cell death (AICD), which requires the transcriptional induction of FasL expression [5-7] and sustained levels of c-Myc [8]. The FasL promoter can be driven by c-Myc overexpression, and functional inhibitors of Myc and its binding partner, Max, inhibit the transcriptional activity of the FasL promoter [9,10]. We identified a non-canonical binding site (ATTCTCT) for c-Myc-Max heterodimers in the FasL promoter, which, when mutated, abolished activity in response to c-Myc. Exchange of the canonical c-Myc responsive elements (CACGTG) in the ornithine decarboxylase (ODC) promoter [11] with the non-canonical sequence in the FasL promoter generated an ODC-FasL promoter that was significantly more responsive to c-Myc than the wild-type ODC promoter. Our findings identify a precise physiological role for c-Myc in the induction of apoptosis as a transcriptional regulator of the FasL gene.
Kasibhatla
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Maxim Research, 6650 Nancy Ridge Drive, San Diego, California 92121, USA. skasibhatla@cytovia.com
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D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016271:Proto-Oncogene Proteins c-myc