Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Inactivation of TGF-β signaling in hepatocytes results in an increased proliferative response after partial hepatectomy

Oncogene volume 24, pages 3028–3041 (2005)Cite this article

Abstract

The transforming growth factor β (TGF-β) signaling pathway, which is activated by the TGF-β receptor complex consisting of type I and type II TGF-β receptors (TGFBR1 and TGFBR2), regulates cell growth and death. TGF-β and components of its signaling pathway, particularly TGFBR2, have been implicated as tumor suppressor genes and important antimitogenic factors in the gastrointestinal tract and liver. An in vivo approach to study these effects has been hindered by the embryonic lethality of Tgfbr2−/− mice and poor viability of the Tgfb1−/− mice. Consequently, we have developed a hepatocyte-specific Tgfbr2 knockout mouse, the Alb-cre Tgfbr2flx/flx mouse, to study the physiologically relevant effects of TGF-β signaling on epithelial cell proliferation in vivo. After 70% hepatectomy, we observed increased proliferation and an increased liver mass : body weight ratio in the Alb-cre Tgfbr2flx/flx mice compared to Tgfbr2flx/flx mice. We also observed decreased expression and increased phosphorylation of p130 in the livers from the Alb-cre Tgfbr2flx/flx mice as well as increased expression of cyclin E, which is transcriptionally regulated, in part, by p130:E2F4. Consistent with these results, in a hepatocyte cell line derived from the Tgfbr2flx/flx mice, we found that TGF-β increases the nuclear localization of E2F4, and presumably the transcriptional repression of the p130:E2F4 complex. Thus, we have demonstrated that TGF-β signaling in vivo regulates the mitogenic response in the regenerating liver, affecting the liver mass : body weight ratio after partial hepatectomy, and that these mitogenic responses are accompanied by alterations in p130 expression and phosphorylation, implicating p130 as one of the proteins regulated in vivo by TGF-β during liver regeneration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  • Akita K, Okuno M, Enya M, Imai S, Moriwaki H, Kawada N, Suzuki Y and Kojima S. . (2002). Gastroenterology, 123, 352–364.

  • Albrecht JH, Rieland BM, Nelsen CJ and Ahonen CL . (1999). Am. J. Physiol., 277, G1207–G1216.

  • Alexandrow M and Moses H . (1995). Cancer Res., 55, 1452–1457.

  • Allen KJ, Reyes R, Demmler K, Mercer JF, Williamson R and Whitehead RH . (2000). J. Gastroenterol. Hepatol., 15, 1325–1332.

  • Barbiroli B and Potter VR . (1971). Science, 172, 738–741.

  • Bedossa P, Peltier E, Terris B, Franco D and Poynard T . (1995). Hepatology, 21, 760–766.

  • Bhowmick NA, Ghiassi M, Aakre M, Brown K, Singh V and Moses HL . (2003). Proc. Natl. Acad. Sci. USA, 100, 15548–15553.

  • Bissell DM, Wang SS, Jarnagin WR and Roll FJ . (1995). J. Clin. Invest., 96, 447–455.

  • Blobe GC, Schiemann WP and Lodish HF . (2000). N. Engl. J. Med., 342, 1350–1358.

  • Bouzahzah B, Fu M, Iavarone A, Factor VM, Thorgeirsson SS and Pestell RG . (2000). Cancer Res., 60, 4531–4537.

  • Braun L, Mead JE, Panzica M, Mikumo R, Bell GI and Fausto N . (1988). Proc. Natl. Acad. Sci. USA, 85, 1539–1543.

  • Carr B, Hayashi I, Branum E and Moses H . (1986). Cancer Res., 46, 2330–2334.

  • Chari RS, Price DT, Sue SR, Meyers WC and Jirtle RL . (1995). Am. J. Surg., 169, 126–131 (discussion 131–132).

  • Chen CR, Kang Y, Siegel PM and Massague J . (2002). Cell, 110, 19–32.

  • Chytil A, Magnuson MA, Wright CV and Moses HL . (2002). Genesis, 32, 73–75.

  • Cipriano SC and Chen YQ . (1998). Oncogene, 17, 1549–1556.

  • Coughlin JP, Austen Jr WG, Donahoe PK and Russell WE . (1987). J. Pediatr. Surg., 22, 566–570.

  • Datto M, Li Y, Panus J, Howe D, Xiong Y and Wang X-F . (1995). Proc. Natl. Acad. Sci. USA, 92, 5545–5549.

  • Derynck R and Zhang YE . (2003). Nature, 425, 577–584.

  • Enami Y, Kato H, Murakami M, Fujioka T, Aoki T, Niiya T, Murai N, Ohtsuka K and Kusano M . (2001). J. Hepatobiliary Pancreat. Surg., 8, 250–258.

  • Ewen ME, Sluss HK, Whitehouse LL and Livingston DM . (1993). Cell, 74, 1009–1020.

  • Factor VM, Kao CY, Santoni-Rugiu E, Woitach JT, Jensen MR and Thorgeirsson SS . (1997). Cancer Res., 57, 2089–2095.

  • Fausto N . (2000). J. Hepatol., 32, 19–31.

  • Fausto N and Webber EM . (1993). Prog. Liver Dis., 11, 115–137.

  • Fynan TM and Reiss M . (1993). Crit. Rev. Oncog., 4, 493–540.

  • Grasl-Kraupp B, Rossmanith W, Ruttkay-Nedecky B, Mullauer L, Kammerer B, Bursch W and Schulte-Hermann R . (1998). Hepatology, 28, 717–726.

  • Hannon G and Beach D . (1994). Nature, 371, 257–261.

  • Henis YI, Moustakas A, Lin HY and Lodish HF . (1994). J. Cell Biol., 126, 139–154.

  • Herrera RE, Makela TP and Weinberg RA . (1996). Mol. Biol. Cell, 7, 1335–1342.

  • Howe PH, Draetta G and Leof EB . (1991). Mol. Cell. Biol., 11, 1185–1194.

  • Iavarone A and Massague J . (1997). Nature, 387, 417–422.

  • Iavarone A and Massague J . (1999). Mol. Cell. Biol., 19, 916–922.

  • Im YH, Kim DH, Kim IY, Factor V, Hahm KB, Anzano M, Jang JJ, Flanders K, Haines DC, Thorgeirsson SS, Sizeland A and Kim SJ . (2001). Cancer Res., 61, 6665–6668.

  • Iwase S, Furukawa Y, Kikuchi J, Nagai M, Terui Y, Nakamura M and Yamada H . (1997). J. Biol. Chem., 272, 12406–12414.

  • Kanzler S, Meyer E, Lohse AW, Schirmacher P, Henninger J, Galle PR and Blessing M . (2001). Oncogene, 20, 5015–5024.

  • Kiss A, Wang NJ, Xie JP and Thorgeirsson SS . (1997). Clin. Cancer Res., 3, 1059–1066.

  • Ko T, Sheng H, Reisman D, Thompson E and Beauchamp R . (1995). Oncogene, 10, 177–184.

  • Kogure K, Zhang YQ, Maeshima A, Suzuki K, Kuwano H and Kojima I . (2000). Hepatology, 31, 916–921.

  • Kurisaki A, Kose S, Yoneda Y, Heldin CH and Moustakas A . (2001). Mol. Biol. Cell, 12, 1079–1091.

  • Li W, Liang X, Leu JI, Kovalovich K, Ciliberto G and Taub R . (2001). Hepatology, 33, 1377–1386.

  • Lin HY, Wang X-F, Ng-Eaton E, Weinberg RA and Lodish HF . (1992). Cell, 68, 775–785.

  • Liu C, Gaca MD, Swenson ES, Vellucci VF, Reiss M and Wells RG . (2003). J. Biol. Chem., 278, 11721–11728.

  • Macias-Silva M, Li W, Leu JI, Crissey MA and Taub RA . (2002). J. Biol. Chem., 21, 21.

  • McMahon J, Richards W, del Campo A, Song M and Thorgeirsson S . (1986). Cancer Res., 46, 4665–4671.

  • Mead JE and Fausto N . (1989). Proc. Natl. Acad. Sci. USA, 86, 1558–1562.

  • Michalopoulos GK and DeFrances MC . (1997). Science, 276, 60–66.

  • Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, Koyama Y and Nagai H . (2001). Gastroenterology, 121, 1300–1309.

  • Moses H, Yang E and Pietonpol J . (1990). Cell, 63, 245–247.

  • Moustakas A and Kardassis D . (1998). Proc. Natl. Acad. Sci. USA, 95, 6733–6738.

  • Nagoshi S, Yasuda H, Suda J, Yamanobe F, Ohno A, Higashio K and Fujiwara K . (1998). J. Gastroenterol. Hepatol., 13, 786–793.

  • Nakamura T, Sakata R, Ueno T, Sata M and Ueno H . (2000). Hepatology, 32, 247–255.

  • Oberhammer F, Froschl G, Tiefenbacher R, Inayat-Hussain SH, Cain K and Stopper H . (1996). Microsc. Res. Tech., 34, 247–258.

  • Oe S, Lemmer ER, Conner EA, Factor VM, Leveen P, Larsson J, Karlsson S and Thorgeirsson SS . (2004). Hepatology, 40, 1098–1105.

  • Pietenpol JA, Holt JT, Stein RW and Moses HL . (1990). Proc. Natl. Acad. Sci. USA, 87, 3758–3762.

  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM and Koff A . (1994). Genes Dev., 8, 9–22.

  • Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD and Magnuson MA . (1999). J. Biol. Chem., 274, 305–315.

  • Reynisdottir I, Polyak K, Iavarone A and Massague J . (1995). Genes Dev., 9, 1831–1845.

  • Richards GM . (1974). Anal. Biochem., 57, 369–376.

  • Russell W . (1988a). J. Cell. Physiol., 35, 253–261.

  • Russell WE . (1988b). J. Cell. Physiol., 135, 253–261.

  • Russell WE and Bucher NL . (1983). Am. J. Physiol., 245, G321–G324.

  • Russell WE, Coffey Jr RJ, Ouellette AJ and Moses HL . (1988). Proc. Natl. Acad. Sci. USA, 85, 5126–5130.

  • Saam JR and Gordon JI . (1999). J. Biol. Chem., 274, 38071–38082.

  • Salvucci M, Lemoine A, Saffroy R, Azoulay D, Lepere B, Gaillard S, Bismuth H, Reynes M and Debuire B . (1999). Oncogene, 18, 181–187.

  • Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, Koh J, Slingerland JM and Stampfer MR . (1997). Mol. Cell. Biol., 17, 2458–2467.

  • Satterwhite DJ, Aakre ME, Gorska AE and Moses HL . (1994). Cell Growth Differ., 5, 789–799.

  • Schulte-Hermann R, Bursch W, Grasl-Kraupp B, Mullauer L and Ruttkay-Nedecky B . (1995). Mutat. Res., 333, 81–87.

  • Scotte M, Masson S, Lyoumi S, Hiron M, Teniere P, Lebreton JP and Daveau M . (1997). Cytokine, 9, 859–867.

  • Shirai Y, Kawata S, Tamura S, Ito N, Tsushima H, Takaishi K, Kiso S and Matsuzawa Y . (1994). Cancer, 73, 2275–2279.

  • Siegel PM and Massague J . (2003). Nat. Rev. Cancer, 3, 807–821.

  • Soriano P . (1999). Nat. Genet., 21, 70–71.

  • Strain A, Hill D and Milner R . (1986). Cell Biol. Int. Rep., 10, 855–860.

  • Swift LL, Farkas MH, Major AS, Valyi-Nagy K, Linton MF and Fazio S . (2001). J. Biol. Chem., 276, 22965–22970.

  • Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR, Letterio JJ and Wakefield LM . (1998). Nat. Med., 4, 802–807.

  • Tedesco D, Lukas J and Reed SI . (2002). Genes Dev., 16, 2946–2957.

  • Ten Dijke P, Goumans M-J, Itoh F and Itoh S . (2002). J. Cell. Physiol., 191, 1–16.

  • Teramoto T, Kiss A and Thorgeirsson SS . (1998). Biochem. Biophys. Res. Commun., 251, 56–60.

  • Tucker RF, Shipley GD, Moses HL and Holley RW . (1984). Science, 226, 705–707.

  • Wakefield LM and Roberts AB . (2002). Curr. Opin. Genet. Dev., 12, 22–29.

  • Webber EM, Bruix J, Pierce RH and Fausto N . (1998). Hepatology, 28, 1226–1234.

  • Wong MH, Saam JR, Stappenbeck TS, Rexer CH and Gordon JI . (2000). Proc. Natl. Acad. Sci. USA, 97, 12601–12606.

  • Wrana J, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang X-F and Massague J . (1992). Cell, 71, 1003–1014.

  • Xu L, Chen YG and Massague J . (2000). Nat. Cell Biol., 2, 559–562.

  • Yagi K, Furuhashi M, Aoki H, Goto D, Kuwano H, Sugamura K, Miyazono K and Kato M . (2002). J. Biol. Chem., 277, 854–861.

Download references

Acknowledgements

This work was supported in part by funding from the National Institutes of Health (RO1 DK60669-01 to WMG and RO1 DK53804 to WER), from the Edward Mallinckrodt Jr Foundation (Mallinckrodt Scholar Award), from the Department of Veterans Affairs Office of R&D Puget Sound Healthcare System (Advanced Research Career Development Award), from the Damon Runyon Cancer Research Foundation (Damon Runyon Lilly Clinical Investigator Award), from the Glaxo Institute of Digestive Health (Basic Science Award) (to WMG), RO1CA85492, and R01 CA102162 (to HLM), and by the Mouse Models of Human Cancer, Digestive Disease Research Center, and by support from the Fred Hutchinson Comprehensive Cancer Center and Vanderbilt Ingram Comprehensive Cancer Center.

Author information

Author notes

  1. Judith Romero-Gallo and Elif G Sozmen: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Vanderbilt University, Nashville, TN, USA

    Judith Romero-Gallo & Robert Whitehead

  2. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Elif G Sozmen & William M Grady

  3. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA

    Anna Chytil & Harold L Moses

  4. Department of Pediatrics, Vanderbilt University, Nashville, TN, USA

    William E Russell

  5. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA

    William E Russell

  6. Department of Pathology, University of Washington Medical School, Seattle, WA, USA

    W Tony Parks, Matthew S Holdren & Momoko F Her

  7. Department of Biostatistics, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Shiva Gautam

  8. Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    Mark Magnuson

  9. Veterans Affairs Puget Sound Healthcare System, Seattle, WA, USA

    William M Grady

Authors
  1. Judith Romero-Gallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elif G Sozmen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Chytil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William E Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Whitehead
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Tony Parks
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthew S Holdren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Momoko F Her
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shiva Gautam
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark Magnuson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Harold L Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. William M Grady
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William M Grady.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Romero-Gallo, J., Sozmen, E., Chytil, A. et al. Inactivation of TGF-β signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene 24, 3028–3041 (2005). https://doi.org/10.1038/sj.onc.1208475

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208475

Keywords

This article is cited by

Search

Advanced search

Quick links