Transcriptional regulation of the ornithine decarboxylase gene by c-Myc/Max/Mad network and retinoblastoma protein interacting with c-Myc.
c-Myc is an oncogenic transcription factor involved in the regulation of cell proliferation, differentiation and apoptosis. The direct targets of c-Myc mediating these various processes are slowly being unravelled. This study indicates that the ornithine decarboxylase (ODC) gene is a physiological transcriptional target of c-Myc in association with induction of cell proliferation and transformation, but not with induction of apoptosis. In addition to the two conserved CACGTG c-Myc-binding sites in the first intron, the CATGTG motif in the 5'-flanking region of the murine odc is also shown to be a functional c-Myc response element. odc is thus a c-Myc target with three binding sites a distance apart. Transient transfection studies with different c-Myc, Max and Mad constructs in COS-7 cells showed that the balance between c-Myc/Max, Max/Max and Max/Mad complexes is crucial for the regulation, resulting in either transactivation or transrepression of an ODC-CAT reporter gene. Transcription of both ODC-CAT and endogenous odc was strongly induced in HeLa cells expressing tetracycline-regulated c-Myc, concomitant with c-Myc promoting the S-phase entry of the cells. Transformation of NIH3T3 cells by c-Ha-ras-(Val12) oncogene was reversed by expression of transcriptionally inactive c-Myc, which was associated with repression of ODC-CAT expression. Further, the c-Myc-induced transactivation of ODC-CAT in COS-7 cells was suppressed by co-expression of the retinoblastoma tumor suppresser pRb, evidently as a result of pRb directly or indirectly interacting with c-Myc. Importantly, the endogenous c-Myc and pRb proteins were also found to associate in Colo 320HSR cells under physiological conditions. These results suggest that c-Myc and pRb can interact in vivo, and may in part control some aspects of cell proliferation and transformation through modulation of odc expression.
Auvinen
Merja
M
Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, P.O. Box 21, 00014, Helsinki, Finland.
Järvinen
Kristiina
K
Hotti
Anneli
A
Okkeri
Juha
J
Laitinen
Jens
J
Jänne
Olli A
OA
Coffino
Philip
P
Bergman
Mathias
M
Andersson
Leif C
LC
Alitalo
Kari
K
Hölttä
Erkki
E
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D016259:Genes, myc / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D026161:MADS Domain Proteins / Q000378:metabolism*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D026161:MADS Domain Proteins; C499330:MAX protein, human; C067850:Myc associated factor X; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C068422:Max protein, mouse; D009955:Ornithine Decarboxylase