Transcription profiling of lung adenocarcinomas of c-myc-transgenic mice: identification of the c-myc regulatory gene network.
BACKGROUND
The transcriptional regulator c-Myc is the most frequently deregulated oncogene in human tumors. Targeted overexpression of this gene in mice results in distinct types of lung adenocarcinomas. By using microarray technology, alterations in the expression of genes were captured based on a female transgenic mouse model in which, indeed, c-Myc overexpression in alveolar epithelium results in the development of bronchiolo-alveolar carcinoma (BAC) and papillary adenocarcinoma (PLAC). In this study, we analyzed exclusively the promoters of induced genes by different in silico methods in order to elucidate the c-Myc transcriptional regulatory network.


RESULTS
We analyzed the promoters of 361 transcriptionally induced genes with respect to c-Myc binding sites and found 110 putative binding sites in 94 promoters. Furthermore, we analyzed the flanking sequences (+/- 100 bp) around the 110 c-Myc binding sites and found Ap2, Zf5, Zic3, and E2f binding sites to be overrepresented in these regions. Then, we analyzed the promoters of 361 induced genes with respect to binding sites of other transcription factors (TFs) which were upregulated by c-Myc overexpression. We identified at least one binding site of at least one of these TFs in 220 promoters, thus elucidating a potential transcription factor network. The analysis correlated well with the significant overexpression of the TFs Atf2, Foxf1a, Smad4, Sox4, Sp3 and Stat5a. Finally, we analyzed promoters of regulated genes which where apparently not regulated by c-Myc or other c-Myc targeted TFs and identified overrepresented Oct1, Mzf1, Ppargamma, Plzf, Ets, and HmgIY binding sites when compared against control promoter background.


CONCLUSIONS
Our in silico data suggest a model of a transcriptional regulatory network in which different TFs act in concert upon c-Myc overexpression. We determined molecular rules for transcriptional regulation to explain, in part, the carcinogenic effect seen in mice overexpressing the c-Myc oncogene.
Reymann
Susanne
S
Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany. reymann@item.fraunhofer.de
Borlak
Jürgen
J
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors