Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 May 24;91(11):4649–4653. doi: 10.1073/pnas.91.11.4649

Adipocyte differentiation selectively represses the serum inducibility of c-jun and junB by reversible transcription-dependent mechanisms.

H Wang 1, R E Scott 1
PMCID: PMC43845  PMID: 8197114

Abstract

Nonterminally differentiated 3T3 T adipocytes are resistant to growth stimulation by 10% (vol/vol) fetal bovine serum even though they can be induced to proliferate with extremely high serum concentrations. We now report that in adipocytes 10% fetal bovine serum also fails to typically induce c-jun or junB. Rather, after 10% fetal bovine serum treatment, c-jun and junB expression is markedly repressed after a brief initial slight induction. Gel mobility shift studies confirm that AP-1 DNA binding activity is inhibited in adipocytes. Repression in c-jun and junB inducibility in adipocytes results from transcriptional mechanisms, can be reversed by treatment with protein synthesis inhibitors or higher serum concentrations, and does not affect c-fos or c-myc expression. These data suggest that adipocyte differentiation selectively and transcriptionally represses the inducibility of c-jun and junB so as to decrease the cell's ability to proliferate in response to 10% fetal bovine serum.

Full text

PDF
4649

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  2. Bengal E., Ransone L., Scharfmann R., Dwarki V. J., Tapscott S. J., Weintraub H., Verma I. M. Functional antagonism between c-Jun and MyoD proteins: a direct physical association. Cell. 1992 Feb 7;68(3):507–519. doi: 10.1016/0092-8674(92)90187-h. [DOI] [PubMed] [Google Scholar]
  3. Brach M. A., Gruss H. J., Sott C., Herrmann F. The mitogenic response to tumor necrosis factor alpha requires c-Jun/AP-1. Mol Cell Biol. 1993 Jul;13(7):4284–4290. doi: 10.1128/mcb.13.7.4284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Castellazzi M., Spyrou G., La Vista N., Dangy J. P., Piu F., Yaniv M., Brun G. Overexpression of c-jun, junB, or junD affects cell growth differently. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8890–8894. doi: 10.1073/pnas.88.20.8890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Diamond L., O'Brien T. G., Rovera G. Inhibition of adipose conversion of 3T3 fibroblasts by tumour promoters. Nature. 1977 Sep 15;269(5625):247–249. doi: 10.1038/269247a0. [DOI] [PubMed] [Google Scholar]
  6. Djian P., Phillips M., Green H. Suppression of SV40-promoted gene expression by differentiation of preadipose cells. Genes Dev. 1988 Oct;2(10):1251–1257. doi: 10.1101/gad.2.10.1251. [DOI] [PubMed] [Google Scholar]
  7. Edwards D. R., Mahadevan L. C. Protein synthesis inhibitors differentially superinduce c-fos and c-jun by three distinct mechanisms: lack of evidence for labile repressors. EMBO J. 1992 Jul;11(7):2415–2424. doi: 10.1002/j.1460-2075.1992.tb05306.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Estervig D. N., Minoo P., Tzen C. Y., Scott R. E. Inhibition of simian virus 40 T-antigen expression by cellular differentiation. J Virol. 1989 Jun;63(6):2718–2725. doi: 10.1128/jvi.63.6.2718-2725.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Freytag S. O., Geddes T. J. Reciprocal regulation of adipogenesis by Myc and C/EBP alpha. Science. 1992 Apr 17;256(5055):379–382. doi: 10.1126/science.256.5055.379. [DOI] [PubMed] [Google Scholar]
  10. Herschman H. R. Primary response genes induced by growth factors and tumor promoters. Annu Rev Biochem. 1991;60:281–319. doi: 10.1146/annurev.bi.60.070191.001433. [DOI] [PubMed] [Google Scholar]
  11. Hoerl B. J., Scott R. E. Nonterminally differentiated cells express decreased growth factor responsiveness. J Cell Physiol. 1989 Apr;139(1):68–75. doi: 10.1002/jcp.1041390111. [DOI] [PubMed] [Google Scholar]
  12. Holt J. T., Gopal T. V., Moulton A. D., Nienhuis A. W. Inducible production of c-fos antisense RNA inhibits 3T3 cell proliferation. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4794–4798. doi: 10.1073/pnas.83.13.4794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hughes M., Sehgal A., Hadman M., Bos T. Heterodimerization with c-Fos is not required for cell transformation of chicken embryo fibroblasts by Jun. Cell Growth Differ. 1992 Dec;3(12):889–897. [PubMed] [Google Scholar]
  14. Kovary K., Bravo R. The jun and fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol. 1991 Sep;11(9):4466–4472. doi: 10.1128/mcb.11.9.4466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lau L. F., Nathans D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1182–1186. doi: 10.1073/pnas.84.5.1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Minoo P., Sullivan W., Solomon L. R., Martin T. E., Toft D. O., Scott R. E. Loss of proliferative potential during terminal differentiation coincides with the decreased abundance of a subset of heterogeneous ribonuclear proteins. J Cell Biol. 1989 Nov;109(5):1937–1946. doi: 10.1083/jcb.109.5.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nishikura K., Murray J. M. Antisense RNA of proto-oncogene c-fos blocks renewed growth of quiescent 3T3 cells. Mol Cell Biol. 1987 Feb;7(2):639–649. doi: 10.1128/mcb.7.2.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Phillips P. D., Pignolo R. J., Cristofalo V. J. Insulin-like growth factor-I: specific binding to high and low affinity sites and mitogenic action throughout the life span of WI-38 cells. J Cell Physiol. 1987 Oct;133(1):135–143. doi: 10.1002/jcp.1041330117. [DOI] [PubMed] [Google Scholar]
  19. Phillips P. D., Pignolo R. J., Nishikura K., Cristofalo V. J. Renewed DNA synthesis in senescent WI-38 cells by expression of an inducible chimeric c-fos construct. J Cell Physiol. 1992 Apr;151(1):206–212. doi: 10.1002/jcp.1041510126. [DOI] [PubMed] [Google Scholar]
  20. Prywes R., Roeder R. G. Inducible binding of a factor to the c-fos enhancer. Cell. 1986 Dec 5;47(5):777–784. doi: 10.1016/0092-8674(86)90520-9. [DOI] [PubMed] [Google Scholar]
  21. Riabowol K. T., Vosatka R. J., Ziff E. B., Lamb N. J., Feramisco J. R. Microinjection of fos-specific antibodies blocks DNA synthesis in fibroblast cells. Mol Cell Biol. 1988 Apr;8(4):1670–1676. doi: 10.1128/mcb.8.4.1670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Riabowol K., Schiff J., Gilman M. Z. Transcription factor AP-1 activity is required for initiation of DNA synthesis and is lost during cellular aging. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):157–161. doi: 10.1073/pnas.89.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rittling S. R., Brooks K. M., Cristofalo V. J., Baserga R. Expression of cell cycle-dependent genes in young and senescent WI-38 fibroblasts. Proc Natl Acad Sci U S A. 1986 May;83(10):3316–3320. doi: 10.1073/pnas.83.10.3316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rose D. W., McCabe G., Feramisco J. R., Adler M. Expression of c-fos and AP-1 activity in senescent human fibroblasts is not sufficient for DNA synthesis. J Cell Biol. 1992 Dec;119(6):1405–1411. doi: 10.1083/jcb.119.6.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sadowski H. B., Wheeler T. T., Young D. A. Gene expression during 3T3-L1 adipocyte differentiation. Characterization of initial responses to the inducing agents and changes during commitment to differentiation. J Biol Chem. 1992 Mar 5;267(7):4722–4731. [PubMed] [Google Scholar]
  26. Scott R. E., Estervig D. N., Tzen C. Y., Minoo P., Maercklein P. B., Hoerl B. J. Nonterminal differentiation represses the neoplastic phenotype in spontaneously and simian virus 40-transformed cells. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1652–1656. doi: 10.1073/pnas.86.5.1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Scott R. E., Florine D. L., Wille J. J., Jr, Yun K. Coupling of growth arrest and differentiation at a distinct state in the G1 phase of the cell cycle: GD. Proc Natl Acad Sci U S A. 1982 Feb;79(3):845–849. doi: 10.1073/pnas.79.3.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Scott R. E., Hoerl B. J., Wille J. J., Jr, Florine D. L., Krawisz B. R., Yun K. Coupling of proadipocyte growth arrest and differentiation. II. A cell cycle model for the physiological control of cell proliferation. J Cell Biol. 1982 Aug;94(2):400–405. doi: 10.1083/jcb.94.2.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sell C., Ptasznik A., Chang C. D., Swantek J., Cristofalo V. J., Baserga R. IGF-1 receptor levels and the proliferation of young and senescent human fibroblasts. Biochem Biophys Res Commun. 1993 Jul 15;194(1):259–265. doi: 10.1006/bbrc.1993.1813. [DOI] [PubMed] [Google Scholar]
  30. Seshadri T., Campisi J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science. 1990 Jan 12;247(4939):205–209. doi: 10.1126/science.2104680. [DOI] [PubMed] [Google Scholar]
  31. Sidhu R. S. Two-dimensional electrophoretic analyses of proteins synthesized during differentiation of 3T3-L1 preadipocytes. J Biol Chem. 1979 Nov 10;254(21):11111–11118. [PubMed] [Google Scholar]
  32. Smith M. J., Prochownik E. V. Inhibition of c-jun causes reversible proliferative arrest and withdrawal from the cell cycle. Blood. 1992 Apr 15;79(8):2107–2115. [PubMed] [Google Scholar]
  33. Subramaniam M., Schmidt L. J., Crutchfield C. E., 3rd, Getz M. J. Negative regulation of serum-responsive enhancer elements. Nature. 1989 Jul 6;340(6228):64–66. doi: 10.1038/340064a0. [DOI] [PubMed] [Google Scholar]
  34. Trouche D., Grigoriev M., Lenormand J. L., Robin P., Leibovitch S. A., Sassone-Corsi P., Harel-Bellan A. Repression of c-fos promoter by MyoD on muscle cell differentiation. Nature. 1993 May 6;363(6424):79–82. doi: 10.1038/363079a0. [DOI] [PubMed] [Google Scholar]
  35. Wang H. L., Scott R. E. Insulin-induced mitogenesis associated with transformation by the SV40 large T antigen. J Cell Physiol. 1991 Apr;147(1):102–110. doi: 10.1002/jcp.1041470114. [DOI] [PubMed] [Google Scholar]
  36. Wang H., Scott R. E. Induction of c-jun independent of PKC, pertussis toxin-sensitive G protein, and polyamines in quiescent SV40-transformed 3T3 T cells. Exp Cell Res. 1992 Nov;203(1):47–55. doi: 10.1016/0014-4827(92)90038-a. [DOI] [PubMed] [Google Scholar]
  37. Wang H., Wang J. Y., Johnson L. R., Scott R. E. Selective induction of c-jun and jun-B but not c-fos or c-myc during mitogenesis in SV40-transformed cells at the predifferentiation growth arrest state. Cell Growth Differ. 1991 Dec;2(12):645–652. [PubMed] [Google Scholar]
  38. Wier M. L., Scott R. E. Aproliferin--a human plasma protein that induces the irreversible loss of proliferative potential associated with terminal differentiation. Am J Pathol. 1986 Dec;125(3):546–554. [PMC free article] [PubMed] [Google Scholar]
  39. Wier M. L., Scott R. E. Defective control of terminal differentiation and its role in carcinogenesis in the 3T3 T proadipocyte stem cell line. Cancer Res. 1985 Jul;45(7):3339–3346. [PubMed] [Google Scholar]
  40. Wier M. L., Scott R. E. Polypeptide changes associated with loss of proliferative potential during the terminal event in differentiation. J Cell Biochem. 1987 Feb;33(2):137–150. doi: 10.1002/jcb.240330208. [DOI] [PubMed] [Google Scholar]
  41. Wier M. L., Scott R. E. Regulation of the terminal event in cellular differentiation: biological mechanisms of the loss of proliferative potential. J Cell Biol. 1986 May;102(5):1955–1964. doi: 10.1083/jcb.102.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ye Z. S., Samuels H. H. Cell- and sequence-specific binding of nuclear proteins to 5'-flanking DNA of the rat growth hormone gene. J Biol Chem. 1987 May 5;262(13):6313–6317. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES