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. 1997 Dec;88(12):1155–1164. doi: 10.1111/j.1349-7006.1997.tb00344.x

Prohibitin Expression Is Decreased in the Regenerating Liver but Not in Chemically Induced Hepatic Tumors in Rats

Satoshi Tanno 1, Ikue Fukuda 1, Yoshinori Saito 1, Katsuhiro Ogawa 1,✉
PMCID: PMC5921338  PMID: 9473733

Abstract

Expression of prohibitin, a growth‐regulatory protein, was immunohistochemically investigated in normal rat tissues, regenerating livers, and chemically induced preneoplastic and neoplastic hepatic lesions. Specific cell types including hepatocytes, striated and smooth muscle cells, cardiac cells, squamous epithelial cells, sebaceous gland cells, hair root outer sheath cells, salivary gland duct epithelial cells, chondrocytes, immature spermatocytes and oocytes were found to be positive. In regenerating livers, prohibitin protein disappeared as early as 3 h after two‐thirds hepatectomy and returned to near the original level by 24 h, while its mRNA level did not markedly vary. The timing of the disappearance was coincident with the expression of c‐myc, suggesting a relation to quiescent hepatocytes entering the cell cycle. However, no pronounced decrease was evident in the most hyperplastic hepatic nodules and hepatocellnlar carcinomas investigated. Examination of 9 rat hepatocellular carcinoma cell lines, 6 hyperplastic hepatic nodules and 5 hepatocellular carcinomas revealed a single case of a base substitution in prohibitin cDNA, identified as a synonymous sense change. The observed abundant expression of prohibitin in quiescent hepatocytes and its rapid loss under conditions of regeneration indicate a growth‐regulatory function, but our results do not suggest any critical role in rat hepatocarcinogenesis.

Keywords: Prohibitin, Liver regeneration, Hepatocarcinogenesis

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REFERENCES

  • 1. ) Lumpkin , C. K.Jr. , McClung , J. K. and Smith , J. R.Entry into S phase is inhibited in human diploid fibroblasts by rat liver poly(A)+RNA . Exp. Cell Res. , 160 , 544 – 549 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Lumpkin , C. K. , Jr. , McClung , J. K. , Pereira‐Smith , O. M. and Smith , J.R.Existence of high abundance anti‐proliferative mRNA's in senescent human diploid fibroblasts . Science , 232 , 393 – 395 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) McClung , J. K. , Danner , D. B. , Stewart , D. A. , Smith , J. R. , Schneider , E. L. , Lumpkin , C. K. , Jr. , DelľOrco , R.and Nuell, M. J.Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver . Biochem. Biophys. Res. Commun. , 164 , 1316 – 1322 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Nuell , M. J. , McClung , J. K. , Smith , J. R. and Danner , D. B.Approach to the isolation of antiproliferative genes . Exp. Gerontol. , 24 , 469 – 476 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) McClung , J. K. , Jupe , E. R. , Liu , X.‐T. and DelľOrco , R. T.Prohibitin: potential role in senescence, development, and tumor suppression . Exp. Gerontoi. , 30 , 99 – 124 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) DelľOrco , R. T. , McClung , J. K. , Jupe , E. R. and Liu , X.–T.Prohibitin andthe senescent phenotype , Exp. Gerontoi. , 31 , 245 – 252 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Nuell , M. J. , Stewart , D. A. , Walker , L. , Friedman , V. , Wood , C. M. , Owens , G. A. , Smith , J. R. , Schneider , E. L. , Delclcar;Orco , R. , Lumpkin , C. K.Jr. , Danner , D. B. and McClung , J. K.Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells . Mol Cell. Biol , 11 , 1372 – 1381 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. ) Jupe , E. R. , Liu , X.‐T. , Kiehlbauch , J. L. , McClung , J. K. and DelľOrco , R. T.Prohibitin antiproliferative activity and lack of heterozygosity in immortalized cell lines . Exp. Cell Res. , 218 , 577 – 580 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Jupe , E. R. , Liu , X.‐T. , Kiehlbauch , J. L. , McClung , J. K. and DelľOrco , R. T.The 3′ untranslated region of pro‐hibitin and cellular immortalization . Exp. Cell Res. , 224 , 128 – 135 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Eveleth , D.D. , Jr. and Marsh , J.L.Sequence and expression of the Cc gene, a member of the dopa decarbox‐ylase gene cluster of Drosophila: possible translational regulation . Nucleic Acids Res. , 15 , 6169 – 6183 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Terashima , M. , Kim , K. M. , Adachi , T. , Nielsen , P. J. , Reth , M. , Kohler , G. and Lamers , M. C.The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin–related protein . EMBO J. , 13 , 3782 – 3792 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Ikonen , E. , Fiedler , K. , Parton , R. G. and Simons , K.Prohibitin, anantiproliferative protein, is localized to mitochondria . FEBS Lett. , 358 , 273 – 277 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Sato , T. , Saito , H. , Swensen , J. , Olifant , A. , Wood , C. , Danner , D. , Sakamoto , T. , Takita , K. , Kasumi , F. , Miki , Y. , Skolnick , M. and Nakamura , Y.The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer . Cancer Res. , 52 , 1643 – 1646 ( 1992. ). [PubMed] [Google Scholar]
  • 14. ) Sato , T. , Sakamoto , T. , Takita , K. , Saito , H. , Okui , K. and Nakamura , Y.The human prohibitin (PHB) gene family and its somatic mutations in human tumors . Genomics , 17 , 762 – 764 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Cliby , W. , Sarkar , G. , Ritland , S. R. , Hartmann , L. , Podratz , K. C. and Jenkins , R. B.Absence of prohibitin gene mutation in human epithelial ovarian tumors . Gynecol Oncol , 50 , 34 – 37 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Asamoto , M. and Cohen , S. M.Prohibitin gene is over‐expressed but not mutated in rat bladder carcinomas and cell lines . Cancer Lett. , 83 , 201 – 207 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) McLean , I. W. and Nakane , P.K.Periodate‐lysine‐paraformaldehyde fixative. A new fixative for immunoelec‐tron microscopy . J. Histochem. Cytochem. , 22 , 1077 – 1083 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Solt , D. and Farber , E.New principle for the analysis of chemical carcinogenesis . Nature , 263 , 701 – 703 ( 1976. ). [Google Scholar]
  • 19. ) Satoh , K. , Hatayama , I. , Tateoka , N. , Tamai , K. , Shimizu , T. , Tatematsu , M. , Ito , N , and Sato , K.Transient induction of single GST‐P positive hepatocytes by DEN . Carcinogenesis , 10 , 2107 – 2111 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Sheffield , V. C. , Cox , D. R. , Lerman , L. S. and Myer , M.Attachment of a 40‐base‐pair G+C–rich sequence (GC‐clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single‐base changes . Proc. Natl Acad. Sci. USA , 86 , 232 – 236 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Fukuda , I. and Ogawa , K.Detection of p53 gene mutations in rat hepatocellular carcinoma cell lines by denaturing gradient gel electrophoresis . Mol. Carcinog. , 7 , 257 – 262 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Ogawa , K. , Solt , D. and Farber , E.Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis . Cancer Res. , 40 , 725 – 733 ( 1980. ). [PubMed] [Google Scholar]
  • 23. ) Pereira–Smith , O. M. and Smith , J. R.Genetic analysis of indefinite division in human cells: identification of four complementation groups . Proc. Natl. Acad. Sci. USA , 85 , 6042 – 6046 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Liu , X.‐T. , Stewart , C. A. , King , R. L. , Danner , D. A. , DelľOrco , R. T.Liu , X.‐T. , Stewart , C. A. , King , R. L. , Danner , D. A. , DelľOrco , R. T. and McClung , J. K.Prohibitin expression during cellular senescence of human diploid fibroblasts . Biochem. Biophys. Res.Commun. , 201 , 409 – 414 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Choongkittaworn , N. M. , Kim , K. H. , Danner , D. B. and Griswold , M. D.Expression of prohibitin in rat seminiferous epithelium . Biol. Reprod. , 49 , 300 – 310 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Grisham , J. W.A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidme–3H . Cancer Res. , 22 , 842 – 849 ( 1962. ). [PubMed] [Google Scholar]
  • 27. ) Rabes , H. M.Kinetics of hepatocellular proliferation as a function of the microvascular structure and functional state of the liver . In “ Hepatotrophic Factors ” ed. Porter R. and Whelan J. , pp. 31 – 53 ( 1977. ). Excerpta Medica; , Amsterdam . [DOI] [PubMed] [Google Scholar]
  • 28. ) Roskams , A. J. , Friedman , V. , Wood , C. M. , Walker , L. , Owens , G. A. , Stewart , D. A. , Altus , M. S. , Danner , D. B. , Liu , X.‐T , and McClung , J. K.Cell cycle activity and expression of prohibitin mRNA . J. Cell. Physiol. , 157 , 289 – 295 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Lumpkin , C. K. , Jr. , Moore , T. L. , Tarpley , M. D. , Taylor , J. M. , Badger , T. M. and McClung , J. K.Acute ethanol and selected growth suppressor transcripts in regenerating liver . Alcohol , 12 , 357 – 362 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Faust , N. and Mead , J. E.Biology of disease. Regulation of liver growth; protooncogenes and transforming growth factors . Lab. Invest. , 60 , 4 – 13 ( 1989. ). [PubMed] [Google Scholar]
  • 31. ) Michalopoulos , G.Liver regeneration . Science , 276 , 60 – 66 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Isomura , H. , Sawada , N. , Nakajima , Y. , Sakamoto , H. , Ikeda , T. , Kojima , T. , Enomoto , K. and Mori , M.Increase in portal flow induced c‐myc expression in isolated perfused rat liver . J. Cell. Physiol , 154 , 329 – 332 ( 1993. ). [DOI] [PubMed] [Google Scholar]

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