Age-dependent alterations of c-fos and growth regulation in human fibroblasts expressing the HPV16 E6 protein.
Open accessAbstract
Normal human cells in culture become senescent after a limited number of population doublings. Senescent cells display characteristic changes in gene expression, among which is a repression of the ability to induce the c-fos gene. We have proposed a two-stage model for cellular senescence in which the mortality stage 1 (M1) mechanism can be overcome by agents that bind both the product of the retinoblastoma susceptibility gene (pRB)-like pocket proteins and p53. In this study we determined whether the repression of c-fos at M1 was downstream of the p53 or pRB-like "arms" of the M1 mechanism. We examined c-fos expression during the entire lifespan of normal human fibroblasts carrying E6 (which binds p53), E7 (which binds pRB), or both E6 and E7 of human papilloma virus type 16. The results indicate a dramatic change in cellular physiology at M1. Before M1, c-fos inducibility is controlled by an E6-independent mechanism that is blocked by E7. After M1, c-fos inducibility becomes dependent on E6 whereas E7 has no effect. In addition, a novel oscillation of c-fos expression with an approximately 2-h periodicity appears in E6-expressing fibroblasts post-M1. Accompanying this shift at M1 is a dramatic change in the ability to divide in low serum. Before M1, E6-expressing fibroblasts growth arrest in 0.3% serum, although they continue dividing under those conditions post-M1. These results demonstrate the unique physiology of fibroblasts during the extended lifespan between M1 and M2 and suggest that p53 might participate in the process that represses the c-fos gene at the onset of cellular senescence.
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Elevated levels of FOSB, PTGS2, IL8, FOS, IL1β, JUNB, and JUN have been associated with senescence and SASP secretion.
“Elevated levels of each of these transcripts have been associated with senescence and SASP secretion [[98], [99], [100], [101], [102], [103], [104]]”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [98]
Cites
Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
LAEMMLI, U. K. (1970) · Nature · doi:10.1038/227680a0 · Cited by 249,961 · see citing works
Raza, H., John, A., & Nemmar, A. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350087 · Cited by 47,311 · see citing works
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508 · see citing works
Specific Association of Human Telomerase Activity with Immortal Cells and Cancer
Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L. C., Coviello, G. M., Wright, W. E., Weinrich, S. L., & Shay, J. W. (1994) · Science · doi:10.1126/science.7605428 · Cited by 7,091 · see citing works
Self-citationThe limited in vitro lifetime of human diploid cell strains
Hayflick, L. (1965) · Experimental Cell Research · doi:10.1016/0014-4827(65)90211-9 · Cited by 5,876 · see citing works
Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750 · see citing works
The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation
Angel, P. E., & Karin, M. (1991) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(91)90011-9 · Cited by 3,390 · see citing works
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
Scheffner, M., Huibregtse, J. M., Vierstra, R. D., & Howley, P. M. (1993) · Cell · doi:10.1016/0092-8674(93)90384-3 · Cited by 2,387 · see citing works
Telomere length predicts replicative capacity of human fibroblasts.
Allsopp, R. C., Vaziri, H., Patterson, C., Goldstein, S., Younglai, E. V., Futcher, A. B., Greider, C. W., & Harley, C. B. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.21.10114 · Cited by 2,200 · see citing works
Counter, C. M., Avilion, A. A., LeFeuvre, C. E., Stewart, N. G., Greider, C. W., Harley, C. B., & Bacchetti, S. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05245.x · Cited by 2,096 · see citing works
Improved retroviral vectors for gene transfer and expression.
Miller, A. D., & Rosman, G. J. (1989) · PubMed · Cited by 1,990 · see citing works
Telomere loss: mitotic clock or genetic time bomb?
Harley, C. B. (1991) · Mutation Research/DNAging · doi:10.1016/0921-8734(91)90018-7 · Cited by 1,139 · see citing works
Telomere end-replication problem and cell aging
Levy, M. Z., Allsopp, R. C., Futcher, A. B., Greider, C. W., & Harley, C. B. (1992) · Journal of Molecular Biology · doi:10.1016/0022-2836(92)90096-3 · Cited by 1,069 · see citing works
Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype.
Gm, M., Sprague, C. A., & Cj, E. (1970) · PubMed · Cited by 1,003 · see citing works
A role for both RB and p53 in the regulation of human cellular senescence*1
SHAY, J. (1991) · Experimental Cell Research · doi:10.1016/0014-4827(91)90453-2 · Cited by 757 · see citing works
Self-citationHuibregtse, J. M., Scheffner, M., & Howley, P. M. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.2.775 · Cited by 553 · see citing works
Wright, W. E., Pereira‐Smith, O. M., & Shay, J. W. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.7.3088 · Cited by 478 · see citing works
Self-citationRepression of c- fos Transcription and an Altered Genetic Program in Senescent Human Fibroblasts
Seshadri, T., & Campisi, J. (1990) · Science · doi:10.1126/science.2104680 · Cited by 477 · see citing works
Inducible production of c-fos antisense RNA inhibits 3T3 cell proliferation.
Holt, J. T., Gopal, T. V., Moulton, A. D., & Nienhuis, A. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.13.4794 · Cited by 439 · see citing works
The jun and fos protein families are both required for cell cycle progression in fibroblasts.
Kovary, K., & Bravo, R. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.9.4466 · Cited by 436 · see citing works
Wild-type p53 can down-modulate the activity of various promoters.
Ginsberg, D., Mechta‐Grigoriou, F., Yaniv, M., & Oren, M. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.22.9979 · Cited by 434 · see citing works
Antisense RNA of proto-oncogene c-fos blocks renewed growth of quiescent 3T3 cells.
Nishikura, K., & Murray, J. M. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.2.639 · Cited by 380 · see citing works
Failure to Phosphorylate the Retinoblastoma Gene Product in Senescent Human Fibroblasts
Stein, G. H., Beeson, M., & Gordon, L. (1990) · Science · doi:10.1126/science.2166342 · Cited by 370 · see citing works
Increased activity of p53 in senescing fibroblasts
Atadja, P., Wong, H., Garkavtsev, I., Veillette, C., & Riabowol, K. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.18.8348 · Cited by 308 · see citing works
Negative regulation of human c-fos expression by thes retinoblastoma gene product
Robbins, P. D., Horowitz, J. M., & Mulligan, R. C. (1990) · Nature · doi:10.1038/346668a0 · Cited by 287 · see citing works
Hara, E., Tsurui, H., Shinozaki, A., Nakada, S., & Oda, K. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(91)91403-y · Cited by 260 · see citing works
Shay, J. W., & Wright, W. E. (1989) · Experimental Cell Research · doi:10.1016/0014-4827(89)90369-8 · Cited by 256 · see citing works
Self-citationMicroinjection of fos-specific antibodies blocks DNA synthesis in fibroblast cells.
Riabowol, K. T., Vosatka, R. J., Ziff, E. B., Lamb, N. J. C., & Feramisco, J. R. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.4.1670 · Cited by 249 · see citing works
Telomere positional effects and the regulation of cellular senescence
Wright, W. E., & Shay, J. W. (1992) · Trends in Genetics · doi:10.1016/0168-9525(92)90232-s · Cited by 246 · see citing works
Self-citationStein, R. W., Corrigan, M. W., Yaciuk, P., Whelan, J., & Moran, E. M. (1990) · Journal of Virology · doi:10.1128/jvi.64.9.4421-4427.1990 · Cited by 241 · see citing works
Shay, J. W., Wright, W. E., Brasiskyte, D., & Haegen, B. A. (1993) · PubMed · Cited by 201 · see citing works
Self-citationHu, E., Mueller, E., Oliviero, S., Papaioannou, V. E., Johnson, R. S., & Spiegelman, B. M. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06608.x · Cited by 175 · see citing works
Time, telomeres and tumours: is cellular senescence more than an anticancer mechanism?
Wright, W. E., & Shay, J. W. (1995) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)89044-3 · Cited by 121 · see citing works
Self-citationCellular aging--clonal senescence. A review (Part I).
Gm, M. (1977) · PubMed Central · Cited by 102 · see citing works
Growth of immortal simian virus 40 tsA-transformed human fibroblasts is temperature dependent.
Radna, R. L., Caton, Y., Jha, K. K., Kaplan, P., Li, G., Traganos, F., & Ozer, H. L. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.7.3093 · Cited by 100 · see citing works
Investigation of the role of G1/S cell cycle mediators in cellular senescence
Afshari, C. A., Vojta, P. J., Annab, L. A., Futreal, P. A., Willard, T. B., & Barrett, J. C. (1993) · Experimental Cell Research · doi:10.1006/excr.1993.1306 · Cited by 100 · see citing works
Expression of c‐fos in NIH3T3 cells is very low but inducible throughout the cell cycle.
Bravo, R., BURCKHARDT, J. J., Curran, T., & Müller, R. (1986) · The EMBO Journal · doi:10.1002/j.1460-2075.1986.tb04269.x · Cited by 94 · see citing works
Repression of the basal c-fos promoter by wild-type p53
Kley, N., Chung, R. Y., Fay, S., Loeffler, J., & Seizinger, B. R. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.15.4083 · Cited by 90 · see citing works
Antisense RNA of Proto-Oncogene c-fos Blocks Renewed Growth of Quiescent 3T3 Cells
Nishikura, K., & Murray, J. M. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.2.639-649.1987 · Cited by 71 · see citing works
Sedman, S. A., Hubbert, N. L., Vass, W. C., Lowy, D. R., & Schiller, J. T. (1992) · Journal of Virology · doi:10.1128/jvi.66.7.4201-4208.1992 · Cited by 70 · see citing works
An altered repertoire of (AP-1) at the onset of replicative senescence
Irving, J., Feng, J., Wistrom, C., Pikaart, M. J., & Villeponteau, B. (1992) · Experimental Cell Research · doi:10.1016/0014-4827(92)90415-5 · Cited by 67 · see citing works
Failure of senescent cells to phosphorylate the RB protein.
Futreal, P. A., & Jc, B. (1991) · PubMed · Cited by 65 · see citing works
Schönthal, A. H., & Feramisco, J. R. (1993) · PubMed · Cited by 60 · see citing works
Interaction of the E6 protein of human papillomavirus with cellular proteins.
Keen, N., Elston, R., & Crawford, L. (1994) · PubMed · Cited by 53 · see citing works
Microinjection of fos-Specific Antibodies Blocks DNA Synthesis in Fibroblast Cells
Riabowol, K. T., Vosatka, R. J., Ziff, E. B., Lamb, N. J. C., & Feramisco, J. R. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.4.1670-1676.1988 · Cited by 53 · see citing works
Activation of the c-fos gene by the HPV16 oncoproteins depends upon the cAMP-response element at -60
Morosov, A., Phelps, W. C., & Raychaudhuri, P. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32327-x · Cited by 44 · see citing works
Re-expression of senescent markers in deinduced reversibly immortalized cells
Shay, J. W., West, M. D., & Wright, W. E. (1992) · Experimental Gerontology · doi:10.1016/0531-5565(92)90003-i · Cited by 39 · see citing works
Self-citationEtscheid, B. G., Foster, S. A., & Galloway, D. A. (1994) · Virology · doi:10.1006/viro.1994.1684 · Cited by 38 · see citing works
Naranjo, J. R., Mellström, B., Auwerx, J. H., Mollinedo, F., & Sassone‐Corsi, P. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.12.3605 · Cited by 36 · see citing works
Phillips, P. D., Pignolo, R. J., Nishikura, K., & Cristofalo, V. J. (1992) · Journal of Cellular Physiology · doi:10.1002/jcp.1041510126 · Cited by 34 · see citing works
Induction of replicative DNA synthesis in quiescent human fibroblasts by DNA damaging agents.
Cohn, S. M., Krawisz, B. R., Dresler, S. L., & Lieberman, M. W. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.15.4828 · Cited by 28 · see citing works
Radna, R. L., Caton, Y., Jha, K. K., Kaplan, P., Li, G., Traganos, F., & Ozer, H. L. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.7.3093-3096.1989 · Cited by 26 · see citing works
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Pantoja, C., & Serrano, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202880 · Cited by 201 · see citing works
Gire, V., & Wynford-Thomas, D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1611 · Cited by 161 · see citing works
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Álvarez-Salas, L. M., Cullinan, A. E., Siwkowski, A. M., HAMPEL, A. E., & DiPaolo, J. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.3.1189 · Cited by 94 · see citing works
Hasebe, T., Sasaki, S., Imoto, S., & Ochiai, A. (2001) · Modern Pathology · doi:10.1038/modpathol.3880310 · Cited by 73 · see citing works
Hasebe, T., Sasaki, S., Imoto, S., & Ochiai, A. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65041-9 · Cited by 70 · see citing works
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Debacq‐Chainiaux, F., Pascal, T. G., Boilan, E., Bastin, C., Bauwens, É., & Toussaint, O. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.02.001 · Cited by 52 · see citing works
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“…IL1 β , JUNB , and JUN expression in PBMCs. Elevated levels of each of these transcripts have been associated with senescence and SASP secretion [98 – 104], with our results indicating downregulation of pathways involved in in fl ammation and cell fate decisions [105,106] to provide suggestive…”
Orr, M. E., Garbarino, V. R., Palavicini, J., Melendez, J., Barthélemy, N. R., He, Y., Kautz, T. F., Lopez‐Cruzan, M., Mathews, J. J., Xu, P., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-3994894/v1 · Cited by 8 · see citing works
- Authors
- Yan, Y., Ouellette, M. M., Shay, J. W., & Wright, W. E.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- Molecular Biology of the Cell
- Published
- 1996-06
- Volume
- 7
- Issue
- 6
- Pages
- 975-983
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC275947
- OpenAlex
- W2126264311
- Cited by
- 9
- References
- 52
- Citations by year
- 2025: 1 · 2024: 1 · 2012: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ag007922-07)
- Medical Research Council
- National Institute on Aging (AG07922)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Keywords
- cellular senescence, c-fos, HPV16 E6, HPV16 E7, p53, retinoblastoma protein, human fibroblasts, growth regulation, oncogenic transformation
- MeSH terms
- Aging, Antigens, Viral, Tumor, Cell Division, Cell Line, Fibroblasts, Gene Expression Regulation, Humans, Mammary Tumor Virus, Mouse, Oncogene Proteins, Viral, Oncogenes, Repressor Proteins, Genes, fos, Papillomaviridae
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