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. 1991 Mar;11(3):1372–1381. doi: 10.1128/mcb.11.3.1372

Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells.

M J Nuell 1, D A Stewart 1, L Walker 1, V Friedman 1, C M Wood 1, G A Owens 1, J R Smith 1, E L Schneider 1, R Dell' Orco 1, C K Lumpkin 1, et al.
PMCID: PMC369408  PMID: 1996099

Abstract

Genes that act inside the cell to negatively regulate proliferation are of great interest because of their implications for such processes as development and cancer, but these genes have been difficult to clone. This report details the cloning and analysis of cDNA for prohibitin, a novel mammalian antiproliferative protein. Microinjection of synthetic prohibitin mRNA blocks entry into S phase in both normal fibroblasts and HeLa cells. Microinjection of an antisense oligonucleotide stimulates entry into S phase. By sequence comparison, the prohibitin gene appears to be the mammalian analog of Cc, a Drosophila gene that is vital for normal development.

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Selected References

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

  1. Baker S. J., Markowitz S., Fearon E. R., Willson J. K., Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. doi: 10.1126/science.2144057. [DOI] [PubMed] [Google Scholar]
  2. Buchberg A. M., Cleveland L. S., Jenkins N. A., Copeland N. G. Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway. Nature. 1990 Sep 20;347(6290):291–294. doi: 10.1038/347291a0. [DOI] [PubMed] [Google Scholar]
  3. Call K. M., Glaser T., Ito C. Y., Buckler A. J., Pelletier J., Haber D. A., Rose E. A., Kral A., Yeger H., Lewis W. H. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9;60(3):509–520. doi: 10.1016/0092-8674(90)90601-a. [DOI] [PubMed] [Google Scholar]
  4. Cate R. L., Mattaliano R. J., Hession C., Tizard R., Farber N. M., Cheung A., Ninfa E. G., Frey A. Z., Gash D. J., Chow E. P. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell. 1986 Jun 6;45(5):685–698. doi: 10.1016/0092-8674(86)90783-x. [DOI] [PubMed] [Google Scholar]
  5. Cawthon R. M., Weiss R., Xu G. F., Viskochil D., Culver M., Stevens J., Robertson M., Dunn D., Gesteland R., O'Connell P. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1):193–201. doi: 10.1016/0092-8674(90)90253-b. [DOI] [PubMed] [Google Scholar]
  6. Dean C., Favreau M., Dunsmuir P., Bedbrook J. Confirmation of the relative expression levels of the Petunia (Mitchell) rbcS genes. Nucleic Acids Res. 1987 Jun 11;15(11):4655–4668. doi: 10.1093/nar/15.11.4655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dippold W. G., Jay G., DeLeo A. B., Khoury G., Old L. J. p53 transformation-related protein: detection by monoclonal antibody in mouse and human cells. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1695–1699. doi: 10.1073/pnas.78.3.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eveleth D. D., Jr, Marsh J. L. Sequence and expression of the Cc gene, a member of the dopa decarboxylase gene cluster of Drosophila: possible translational regulation. Nucleic Acids Res. 1986 Aug 11;14(15):6169–6183. doi: 10.1093/nar/14.15.6169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  10. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  11. Fornace A. J., Jr, Nebert D. W., Hollander M. C., Luethy J. D., Papathanasiou M., Fargnoli J., Holbrook N. J. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol. 1989 Oct;9(10):4196–4203. doi: 10.1128/mcb.9.10.4196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., Dryja T. P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. doi: 10.1038/323643a0. [DOI] [PubMed] [Google Scholar]
  13. Fung Y. K., Murphree A. L., T'Ang A., Qian J., Hinrichs S. H., Benedict W. F. Structural evidence for the authenticity of the human retinoblastoma gene. Science. 1987 Jun 26;236(4809):1657–1661. doi: 10.1126/science.2885916. [DOI] [PubMed] [Google Scholar]
  14. Gearing D. P., Gough N. M., King J. A., Hilton D. J., Nicola N. A., Simpson R. J., Nice E. C., Kelso A., Metcalf D. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J. 1987 Dec 20;6(13):3995–4002. doi: 10.1002/j.1460-2075.1987.tb02742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gessler M., Poustka A., Cavenee W., Neve R. L., Orkin S. H., Bruns G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. doi: 10.1038/343774a0. [DOI] [PubMed] [Google Scholar]
  16. Giordano T., Foster D. N. Identification of a highly abundant cDNA isolated from senescent WI-38 cells. Exp Cell Res. 1989 Dec;185(2):399–406. doi: 10.1016/0014-4827(89)90310-8. [DOI] [PubMed] [Google Scholar]
  17. Gray P. W., Leung D. W., Pennica D., Yelverton E., Najarian R., Simonsen C. C., Derynck R., Sherwood P. J., Wallace D. M., Berger S. L. Expression of human immune interferon cDNA in E. coli and monkey cells. Nature. 1982 Feb 11;295(5849):503–508. doi: 10.1038/295503a0. [DOI] [PubMed] [Google Scholar]
  18. Hansen M. F., Cavenee W. K. Tumor suppressors: recessive mutations that lead to cancer. Cell. 1988 Apr 22;53(2):173–174. doi: 10.1016/0092-8674(88)90376-5. [DOI] [PubMed] [Google Scholar]
  19. Huang H. J., Yee J. K., Shew J. Y., Chen P. L., Bookstein R., Friedmann T., Lee E. Y., Lee W. H. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science. 1988 Dec 16;242(4885):1563–1566. doi: 10.1126/science.3201247. [DOI] [PubMed] [Google Scholar]
  20. Kitayama H., Sugimoto Y., Matsuzaki T., Ikawa Y., Noda M. A ras-related gene with transformation suppressor activity. Cell. 1989 Jan 13;56(1):77–84. doi: 10.1016/0092-8674(89)90985-9. [DOI] [PubMed] [Google Scholar]
  21. Klein G. The approaching era of the tumor suppressor genes. Science. 1987 Dec 11;238(4833):1539–1545. doi: 10.1126/science.3317834. [DOI] [PubMed] [Google Scholar]
  22. Lee W. H., Bookstein R., Hong F., Young L. J., Shew J. Y., Lee E. Y. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987 Mar 13;235(4794):1394–1399. doi: 10.1126/science.3823889. [DOI] [PubMed] [Google Scholar]
  23. Lee W. H., Shew J. Y., Hong F. D., Sery T. W., Donoso L. A., Young L. J., Bookstein R., Lee E. Y. The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature. 1987 Oct 15;329(6140):642–645. doi: 10.1038/329642a0. [DOI] [PubMed] [Google Scholar]
  24. Lumpkin C. K., Jr, McClung J. K., Pereira-Smith O. M., Smith J. R. Existence of high abundance antiproliferative mRNA's in senescent human diploid fibroblasts. Science. 1986 Apr 18;232(4748):393–395. doi: 10.1126/science.2421407. [DOI] [PubMed] [Google Scholar]
  25. Lumpkin C. K., Jr, McClung J. K., Smith J. R. Entry into S phase is inhibited in human fibroblasts by rat liver poly(A)+RNA. Exp Cell Res. 1985 Oct;160(2):544–549. doi: 10.1016/0014-4827(85)90201-0. [DOI] [PubMed] [Google Scholar]
  26. McClung J. K., Danner D. B., Stewart D. A., Smith J. R., Schneider E. L., Lumpkin C. K., Dell'Orco R. T., Nuell M. J. Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1316–1322. doi: 10.1016/0006-291x(89)91813-5. [DOI] [PubMed] [Google Scholar]
  27. Mercer W. E., Shields M. T., Amin M., Sauve G. J., Appella E., Romano J. W., Ullrich S. J. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6166–6170. doi: 10.1073/pnas.87.16.6166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Moses H. L., Yang E. Y., Pietenpol J. A. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell. 1990 Oct 19;63(2):245–247. doi: 10.1016/0092-8674(90)90155-8. [DOI] [PubMed] [Google Scholar]
  29. Oren M., Levine A. J. Molecular cloning of a cDNA specific for the murine p53 cellular tumor antigen. Proc Natl Acad Sci U S A. 1983 Jan;80(1):56–59. doi: 10.1073/pnas.80.1.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pepperkok R., Schneider C., Philipson L., Ansorge W. Single cell assay with an automated capillary microinjection system. Exp Cell Res. 1988 Oct;178(2):369–376. doi: 10.1016/0014-4827(88)90406-5. [DOI] [PubMed] [Google Scholar]
  32. Pepperkok R., Zanetti M., King R., Delia D., Ansorge W., Philipson L., Schneider C. Automatic microinjection system facilitates detection of growth inhibitory mRNA. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6748–6752. doi: 10.1073/pnas.85.18.6748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ponder B. Cancer. Gene losses in human tumours. Nature. 1988 Sep 29;335(6189):400–402. doi: 10.1038/335400a0. [DOI] [PubMed] [Google Scholar]
  34. Rizzino A. Transforming growth factor-beta: multiple effects on cell differentiation and extracellular matrices. Dev Biol. 1988 Dec;130(2):411–422. doi: 10.1016/0012-1606(88)90337-5. [DOI] [PubMed] [Google Scholar]
  35. Rose E. A., Glaser T., Jones C., Smith C. L., Lewis W. H., Call K. M., Minden M., Champagne E., Bonetta L., Yeger H. Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene. Cell. 1990 Feb 9;60(3):495–508. doi: 10.1016/0092-8674(90)90600-j. [DOI] [PubMed] [Google Scholar]
  36. Rotter V., Witte O. N., Coffman R., Baltimore D. Abelson murine leukemia virus-induced tumors elicit antibodies against a host cell protein, P50. J Virol. 1980 Nov;36(2):547–555. doi: 10.1128/jvi.36.2.547-555.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Russell P., Nurse P. Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell. 1987 May 22;49(4):559–567. doi: 10.1016/0092-8674(87)90458-2. [DOI] [PubMed] [Google Scholar]
  38. Russell P., Nurse P. cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell. 1986 Apr 11;45(1):145–153. doi: 10.1016/0092-8674(86)90546-5. [DOI] [PubMed] [Google Scholar]
  39. Sager R. Tumor suppressor genes: the puzzle and the promise. Science. 1989 Dec 15;246(4936):1406–1412. doi: 10.1126/science.2574499. [DOI] [PubMed] [Google Scholar]
  40. Schaefer R., Iyer J., Iten E., Nirkko A. C. Partial reversion of the transformed phenotype in HRAS-transfected tumorigenic cells by transfer of a human gene. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1590–1594. doi: 10.1073/pnas.85.5.1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schneider C., King R. M., Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988 Sep 9;54(6):787–793. doi: 10.1016/s0092-8674(88)91065-3. [DOI] [PubMed] [Google Scholar]
  42. Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
  43. Sporn M. B., Roberts A. B. Transforming growth factor-beta: new chemical forms and new biological roles. Biofactors. 1988 Jan;1(1):89–93. [PubMed] [Google Scholar]
  44. Stewart D. A., Blackman M. R., Kowatch M. A., Danner D. B., Roth G. S. Discordant effects of aging on prolactin and luteinizing hormone-beta messenger ribonucleic acid levels in the female rat. Endocrinology. 1990 Feb;126(2):773–778. doi: 10.1210/endo-126-2-773. [DOI] [PubMed] [Google Scholar]
  45. Wallace M. R., Marchuk D. A., Andersen L. B., Letcher R., Odeh H. M., Saulino A. M., Fountain J. W., Brereton A., Nicholson J., Mitchell A. L. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990 Jul 13;249(4965):181–186. doi: 10.1126/science.2134734. [DOI] [PubMed] [Google Scholar]
  46. Wang E. Rapid disappearance of statin, a nonproliferating and senescent cell-specific protein, upon reentering the process of cell cycling. J Cell Biol. 1985 Nov;101(5 Pt 1):1695–1701. doi: 10.1083/jcb.101.5.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Xu G. F., O'Connell P., Viskochil D., Cawthon R., Robertson M., Culver M., Dunn D., Stevens J., Gesteland R., White R. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990 Aug 10;62(3):599–608. doi: 10.1016/0092-8674(90)90024-9. [DOI] [PubMed] [Google Scholar]
  48. Zarling J. M., Shoyab M., Marquardt H., Hanson M. B., Lioubin M. N., Todaro G. J. Oncostatin M: a growth regulator produced by differentiated histiocytic lymphoma cells. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9739–9743. doi: 10.1073/pnas.83.24.9739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. von Heijne G. Patterns of amino acids near signal-sequence cleavage sites. Eur J Biochem. 1983 Jun 1;133(1):17–21. doi: 10.1111/j.1432-1033.1983.tb07424.x. [DOI] [PubMed] [Google Scholar]

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