title: Differentiation modulates the balance of positive and negative Jun/AP-1 DNA binding activities to regulate cellular proliferative potential: different effects in nontransformed and transformed cells.
abstract: Differentiation of 3T3T cells into adipocytes results in the progressive repression of growth factor responsiveness. This is associated with the transcriptional repression of the inducibility of c-jun and junB expression by serum. In contrast, differentiation of SV-40 large T antigen-transformed 3T3T cells (CSV3-1) does not repress growth factor responsiveness nor c-jun or junB inducibility even though CSV3-1 cells can differentiate into adipocytes. To better explain these observations, we have studied compositional changes in AP-1 DNA binding activity attributed to c-Jun, JunB, and JunD during the differentiation process in 3T3T and CSV3-1 cells. The results show that in nontransformed 3T3T cells, differentiation represses AP-1 DNA binding activity via a proportionate downregulation of c-Jun, JunB, and JunD. In contrast, in CSV3-1 cells, AP-1 DNA binding activity increases twofold during differentiation, which is accounted for by an increase in JunD with no change in c-Jun and JunB. If c-Jun and JunB serve as positive regulators and JunD serves as a negative regulator for cell proliferation as suggested by previous studies, the repression of JunD expression in differentiating CSV3-1 cells should be mitogenic because decreasing JunD/AP-1 DNA binding activity would allow c-Jun/AP-1 and JunB/AP-1 DNA binding activities to be dominant. The results confirm this prediction showing that antisense junD oligodeoxyribonucleotides are mitogenic for differentiating CSV3-1 cells whereas antisense c-jun and junB inhibit mitogenesis. These data support the conclusion that differentiation can regulate cellular proliferative potential by modulating the balance of positive and negative Jun/AP-1 DNA binding activities in distinct ways in nontransformed and transformed cells.
authors.affiliation: Department of Pathology, The University of Tennessee Medical Center, Memphis 38163, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Xie
authors.forename: R E
authors.initials: RE
authors.lastname: Scott
mesh_terms: D016475:3T3 Cells / Q000737:chemistry / Q000166:cytology*; D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed / Q000737:chemistry / Q000166:cytology; D016373:DNA, Antisense / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000032:analysis / Q000235:genetics*; D014170:Transformation, Genetic
chemical_list: D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1