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. 1993 Jul;13(7):4157–4166. doi: 10.1128/mcb.13.7.4157

Proliferative activation of quiescent Rat-1A cells by delta FosB.

Y Nakabeppu 1, S Oda 1, M Sekiguchi 1
PMCID: PMC359965  PMID: 8321220

Abstract

Fos and Jun transcription factors are induced during the normal course of the proliferative response of quiescent cells to serum or to growth factors. We have shown that delta FosB, an alternatively spliced form of FosB, is formed as rapidly as FosB in serum-stimulated Rat-1A cells. Although delta FosB lacks the C-terminal region of FosB carrying the transactivation function, constitutive expression of delta FosB transforms Rat-1A cells as does expression of FosB. The transforming ability of delta FosB suggests that delta FosB may lead to proliferative activation of quiescent cells without activating AP-1-responsive genes. To address this question, FosB or delta FosB was expressed as a fusion protein with the ligand binding domain of the human estrogen receptor (ER) in Rat-1A cells. After estrogen treatment, the fusion protein accumulates in nuclei and forms stable complexes with Jun proteins. We have shown that ER-delta FosB or to a lesser extent ER-FosB triggers quiescent Rat-1A cells to transit G1, initiate DNA replication, and ultimately undergo cell division at least once. Since ER-FosB, but not ER-delta FosB, induced expression of the AP-1-responsive transin/stromelysin gene, we concluded that the N-terminal region and the DNA binding domain of FosB or delta FosB itself have the potential to regulate cell proliferation and that the transactivation function carried by the C-terminal region of FosB is not essential for the proliferative activation of quiescent cells.

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Selected References

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

  1. Alani R., Brown P., Binétruy B., Dosaka H., Rosenberg R. K., Angel P., Karin M., Birrer M. J. The transactivating domain of the c-Jun proto-oncoprotein is required for cotransformation of rat embryo cells. Mol Cell Biol. 1991 Dec;11(12):6286–6295. doi: 10.1128/mcb.11.12.6286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bohmann D., Tjian R. Biochemical analysis of transcriptional activation by Jun: differential activity of c- and v-Jun. Cell. 1989 Nov 17;59(4):709–717. doi: 10.1016/0092-8674(89)90017-2. [DOI] [PubMed] [Google Scholar]
  3. Cavalieri F., Goldfarb M. Growth factor-deprived BALB/c 3T3 murine fibroblasts can enter the S phase after induction of c-myc gene expression. Mol Cell Biol. 1987 Oct;7(10):3554–3560. doi: 10.1128/mcb.7.10.3554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Curran T., Franza B. R., Jr Fos and Jun: the AP-1 connection. Cell. 1988 Nov 4;55(3):395–397. doi: 10.1016/0092-8674(88)90024-4. [DOI] [PubMed] [Google Scholar]
  7. DePamphilis M. L. Transcriptional elements as components of eukaryotic origins of DNA replication. Cell. 1988 Mar 11;52(5):635–638. doi: 10.1016/0092-8674(88)90398-4. [DOI] [PubMed] [Google Scholar]
  8. Dobrazanski P., Noguchi T., Kovary K., Rizzo C. A., Lazo P. S., Bravo R. Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts. Mol Cell Biol. 1991 Nov;11(11):5470–5478. doi: 10.1128/mcb.11.11.5470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eckert R. L., Katzenellenbogen B. S. Effects of estrogens and antiestrogens on estrogen receptor dynamics and the induction of progesterone receptor in MCF-7 human breast cancer cells. Cancer Res. 1982 Jan;42(1):139–144. [PubMed] [Google Scholar]
  10. Eilers M., Picard D., Yamamoto K. R., Bishop J. M. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature. 1989 Jul 6;340(6228):66–68. doi: 10.1038/340066a0. [DOI] [PubMed] [Google Scholar]
  11. Eilers M., Schirm S., Bishop J. M. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J. 1991 Jan;10(1):133–141. doi: 10.1002/j.1460-2075.1991.tb07929.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Evan G. I., Wyllie A. H., Gilbert C. S., Littlewood T. D., Land H., Brooks M., Waters C. M., Penn L. Z., Hancock D. C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. doi: 10.1016/0092-8674(92)90123-t. [DOI] [PubMed] [Google Scholar]
  13. Field S. J., Johnson R. S., Mortensen R. M., Papaioannou V. E., Spiegelman B. M., Greenberg M. E. Growth and differentiation of embryonic stem cells that lack an intact c-fos gene. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9306–9310. doi: 10.1073/pnas.89.19.9306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Financsek I., Mizumoto K., Muramatsu M. Nucleotide sequence of the transcription initiation region of a rat ribosomal RNA gene. Gene. 1982 May;18(2):115–122. doi: 10.1016/0378-1119(82)90109-3. [DOI] [PubMed] [Google Scholar]
  15. Granger-Schnarr M., Benusiglio E., Schnarr M., Sassone-Corsi P. Transformation and transactivation suppressor activity of the c-Jun leucine zipper fused to a bacterial repressor. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4236–4239. doi: 10.1073/pnas.89.10.4236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Guo Z. S., DePamphilis M. L. Specific transcription factors stimulate simian virus 40 and polyomavirus origins of DNA replication. Mol Cell Biol. 1992 Jun;12(6):2514–2524. doi: 10.1128/mcb.12.6.2514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hartl M., Vogt P. K. Oncogenic transformation by Jun: role of transactivation and homodimerization. Cell Growth Differ. 1992 Dec;3(12):899–908. [PubMed] [Google Scholar]
  18. Hayakawa H., Koike G., Sekiguchi M. Expression and cloning of complementary DNA for a human enzyme that repairs O6-methylguanine in DNA. J Mol Biol. 1990 Jun 20;213(4):739–747. doi: 10.1016/S0022-2836(05)80260-8. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Håvarstein L. S., Morgan I. M., Wong W. Y., Vogt P. K. Mutations in the Jun delta region suggest an inverse correlation between transformation and transcriptional activation. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):618–622. doi: 10.1073/pnas.89.2.618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jonat C., Rahmsdorf H. J., Park K. K., Cato A. C., Gebel S., Ponta H., Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990 Sep 21;62(6):1189–1204. doi: 10.1016/0092-8674(90)90395-u. [DOI] [PubMed] [Google Scholar]
  22. Kerr L. D., Holt J. T., Matrisian L. M. Growth factors regulate transin gene expression by c-fos-dependent and c-fos-independent pathways. Science. 1988 Dec 9;242(4884):1424–1427. doi: 10.1126/science.2462278. [DOI] [PubMed] [Google Scholar]
  23. Kimura G., Itagaki A., Summers J. Rat cell line 3y1 and its virogenic polyoma- and sv40- transformed derivatives. Int J Cancer. 1975 Apr 15;15(4):694–706. doi: 10.1002/ijc.2910150419. [DOI] [PubMed] [Google Scholar]
  24. Kleid D. G., Yansura D., Small B., Dowbenko D., Moore D. M., Grubman M. J., McKercher P. D., Morgan D. O., Robertson B. H., Bachrach H. L. Cloned viral protein vaccine for foot-and-mouth disease: responses in cattle and swine. Science. 1981 Dec 4;214(4525):1125–1129. doi: 10.1126/science.6272395. [DOI] [PubMed] [Google Scholar]
  25. Kovary K., Bravo R. Existence of different Fos/Jun complexes during the G0-to-G1 transition and during exponential growth in mouse fibroblasts: differential role of Fos proteins. Mol Cell Biol. 1992 Nov;12(11):5015–5023. doi: 10.1128/mcb.12.11.5015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Kovary K., Rizzo C. A., Ryseck R. P., Noguchi T., Raynoschek C., Pelosin J. M., Bravo R. Constitutive expression of FosB and its short form, FosB/SF, induces malignant cell transformation in rat-1A cells. New Biol. 1991 Sep;3(9):870–879. [PubMed] [Google Scholar]
  28. Kumar V., Green S., Staub A., Chambon P. Localisation of the oestradiol-binding and putative DNA-binding domains of the human oestrogen receptor. EMBO J. 1986 Sep;5(9):2231–2236. doi: 10.1002/j.1460-2075.1986.tb04489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  30. Lewin B. Oncogenic conversion by regulatory changes in transcription factors. Cell. 1991 Jan 25;64(2):303–312. doi: 10.1016/0092-8674(91)90640-k. [DOI] [PubMed] [Google Scholar]
  31. Li L., Chambard J. C., Karin M., Olson E. N. Fos and Jun repress transcriptional activation by myogenin and MyoD: the amino terminus of Jun can mediate repression. Genes Dev. 1992 Apr;6(4):676–689. doi: 10.1101/gad.6.4.676. [DOI] [PubMed] [Google Scholar]
  32. Lucibello F. C., Neuberg M., Jenuwein T., Müller R. Multiple regions of v-Fos protein involved in the activation of AP1-dependent transcription: is trans-activation crucial for transformation? New Biol. 1991 Jul;3(7):671–677. [PubMed] [Google Scholar]
  33. Lucibello F. C., Slater E. P., Jooss K. U., Beato M., Müller R. Mutual transrepression of Fos and the glucocorticoid receptor: involvement of a functional domain in Fos which is absent in FosB. EMBO J. 1990 Sep;9(9):2827–2834. doi: 10.1002/j.1460-2075.1990.tb07471.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Marshall C. J. Tumor suppressor genes. Cell. 1991 Jan 25;64(2):313–326. doi: 10.1016/0092-8674(91)90641-b. [DOI] [PubMed] [Google Scholar]
  35. Matrisian L. M., Leroy P., Ruhlmann C., Gesnel M. C., Breathnach R. Isolation of the oncogene and epidermal growth factor-induced transin gene: complex control in rat fibroblasts. Mol Cell Biol. 1986 May;6(5):1679–1686. doi: 10.1128/mcb.6.5.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Morgan I. M., Ransone L. J., Bos T. J., Verma I. M., Vogt P. K. Transformation by Jun: requirement for leucine zipper, basic region and transactivation domain and enhancement by Fos. Oncogene. 1992 Jun;7(6):1119–1125. [PubMed] [Google Scholar]
  37. Mumberg D., Lucibello F. C., Schuermann M., Müller R. Alternative splicing of fosB transcripts results in differentially expressed mRNAs encoding functionally antagonistic proteins. Genes Dev. 1991 Jul;5(7):1212–1223. doi: 10.1101/gad.5.7.1212. [DOI] [PubMed] [Google Scholar]
  38. Murakami Y., Satake M., Yamaguchi-Iwai Y., Sakai M., Muramatsu M., Ito Y. The nuclear protooncogenes c-jun and c-fos as regulators of DNA replication. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3947–3951. doi: 10.1073/pnas.88.9.3947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Murphy T. H., Worley P. F., Nakabeppu Y., Christy B., Gastel J., Baraban J. M. Synaptic regulation of immediate early gene expression in primary cultures of cortical neurons. J Neurochem. 1991 Dec;57(6):1862–1872. doi: 10.1111/j.1471-4159.1991.tb06396.x. [DOI] [PubMed] [Google Scholar]
  40. Nakabeppu Y., Nathans D. A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity. Cell. 1991 Feb 22;64(4):751–759. doi: 10.1016/0092-8674(91)90504-r. [DOI] [PubMed] [Google Scholar]
  41. Nakabeppu Y., Nathans D. The basic region of Fos mediates specific DNA binding. EMBO J. 1989 Dec 1;8(12):3833–3841. doi: 10.1002/j.1460-2075.1989.tb08561.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Nakabeppu Y., Ryder K., Nathans D. DNA binding activities of three murine Jun proteins: stimulation by Fos. Cell. 1988 Dec 2;55(5):907–915. doi: 10.1016/0092-8674(88)90146-8. [DOI] [PubMed] [Google Scholar]
  43. Oliviero S., Robinson G. S., Struhl K., Spiegelman B. M. Yeast GCN4 as a probe for oncogenesis by AP-1 transcription factors: transcriptional activation through AP-1 sites is not sufficient for cellular transformation. Genes Dev. 1992 Sep;6(9):1799–1809. doi: 10.1101/gad.6.9.1799. [DOI] [PubMed] [Google Scholar]
  44. Picard D., Salser S. J., Yamamoto K. R. A movable and regulable inactivation function within the steroid binding domain of the glucocorticoid receptor. Cell. 1988 Sep 23;54(7):1073–1080. doi: 10.1016/0092-8674(88)90122-5. [DOI] [PubMed] [Google Scholar]
  45. Ransone L. J., Verma I. M. Nuclear proto-oncogenes fos and jun. Annu Rev Cell Biol. 1990;6:539–557. doi: 10.1146/annurev.cb.06.110190.002543. [DOI] [PubMed] [Google Scholar]
  46. Schuermann M., Neuberg M., Hunter J. B., Jenuwein T., Ryseck R. P., Bravo R., Müller R. The leucine repeat motif in Fos protein mediates complex formation with Jun/AP-1 and is required for transformation. Cell. 1989 Feb 10;56(3):507–516. doi: 10.1016/0092-8674(89)90253-5. [DOI] [PubMed] [Google Scholar]
  47. Schüle R., Rangarajan P., Kliewer S., Ransone L. J., Bolado J., Yang N., Verma I. M., Evans R. M. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell. 1990 Sep 21;62(6):1217–1226. doi: 10.1016/0092-8674(90)90397-w. [DOI] [PubMed] [Google Scholar]
  48. Schüle R., Umesono K., Mangelsdorf D. J., Bolado J., Pike J. W., Evans R. M. Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene. Cell. 1990 May 4;61(3):497–504. doi: 10.1016/0092-8674(90)90531-i. [DOI] [PubMed] [Google Scholar]
  49. Shiroki K., Segawa K., Koita Y., Shibuya M. Neoplastic transformation of rat 3Y1 cells by a transcriptionally activated human c-myc gene and stabilization of p53 cellular tumor antigen in the transformed cells. Mol Cell Biol. 1986 Dec;6(12):4379–4386. doi: 10.1128/mcb.6.12.4379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Webster N. J., Green S., Jin J. R., Chambon P. The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell. 1988 Jul 15;54(2):199–207. doi: 10.1016/0092-8674(88)90552-1. [DOI] [PubMed] [Google Scholar]
  51. Wisdom R., Yen J., Rashid D., Verma I. M. Transformation by FosB requires a trans-activation domain missing in FosB2 that can be substituted by heterologous activation domains. Genes Dev. 1992 Apr;6(4):667–675. doi: 10.1101/gad.6.4.667. [DOI] [PubMed] [Google Scholar]
  52. Yang-Yen H. F., Chambard J. C., Sun Y. L., Smeal T., Schmidt T. J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990 Sep 21;62(6):1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]
  53. Yen J., Wisdom R. M., Tratner I., Verma I. M. An alternative spliced form of FosB is a negative regulator of transcriptional activation and transformation by Fos proteins. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5077–5081. doi: 10.1073/pnas.88.12.5077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yoshida T., Shindo Y., Ohta K., Iba H. Identification of a small region of the v-fos gene product that is sufficient for transforming potential and growth-stimulating activity. Oncogene Res. 1989;5(2):79–89. [PubMed] [Google Scholar]
  55. Zerial M., Toschi L., Ryseck R. P., Schuermann M., Müller R., Bravo R. The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity. EMBO J. 1989 Mar;8(3):805–813. doi: 10.1002/j.1460-2075.1989.tb03441.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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