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:

Triggering of p73-dependent apoptosis in osteosarcoma is under the control of E2Fs–pRb2/p130 complexes

Oncogene volume 22, pages 3518–3529 (2003)Cite this article

Abstract

Mechanisms underlying multidrug resistance (MDR), one of the major causes of cancer treatment failure, are still poorly understood. We selected the osteosarcoma MDR HosDXR150 cell line by culturing Hos cells in the presence of increasing doxorubicin doses and showed that it is crossresistant to vinblastine. Similarly to the Hos parental cell line, HosDXR150 cells present mutated p53, functionally inactivated pRb/p105 and wild-type pRb2/p130. Owing to p53 mutation, MDR-1 gene, codifying for P-glycoprotein, is upregulated. Evasion of apoptosis in HosDXR150 cells is only partially explained by drug extrusion because of P-glycoprotein overexpression. Analysis of gene expression level profiles showed that parental cell line undergoes apoptosis through an E2F1/p73-dependent pathway while its resistant variant evades it. This result can be explained by the presence of distinct E2Fs–pRb2/p130 complexes on the p73 promoter. Namely, in Hos p73 transcription is activated by E2F1–Rb2/p130–p300 complexes, while in HosDXR150 it is kept repressed by E2F4–Rb2/p130–HDAC1 complexes.

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

Similar content being viewed by others

References

  • An B, Jin JR, Lin P and Dou QP . (1996). FEBS Lett., 399, 158–162.

  • Bellan C, Lazzi S, Ferrari F, Stumpo M, Bartolomei S, Toti P, Leoncini L, Tosi GM, Cevenini G, Cinti C, Trimarchi C, Giordano, Kraft R, Laissue J and Cottier H . (2002). Inv. Ophthal. Visual Sci., 43, 3602–3608.

  • Chan HM, Krstic-Demonacos M, Smith L, Demonacos C and LaThangue NB . (2001). Nat Cell Biol., 3, 667–674.

  • Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesmann MM and Roninson IB . (1986). Cell, 47, 381–389.

  • Cinti C, Claudio PP, De Luca A, Cuccurese M, Howard CM, D'Esposito M, Paggi M, La Sala D, Azzoni L, Halazonetis T, Giordano A and Maraldi NM . (2000). Onocogene, 19, 5098–5105.

  • Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA, Fontemaggi G, Fanciulli M, Schiltz L, Blandino G, Balsano C and Levrero M . (2002). Mol. Cell., 9, 175–186.

  • Cress WW and Seto E . (2000). J. Cell Physiol., 184, 1–16.

  • Dou QP and An B . (1998). Frontiers Biosci., 3, d419–d430.

  • Dyson N . (1998). Gen. Dev., 12, 2245–2262.

  • Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A and Trouche D . (1998). Proc. Natl. Acad. Sci. USA, 95, 104–193.

  • Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey JH and Meyers PA . (1999). J. Clin. Oncol., 17, 2781–2788.

  • Gottesman MM and Pastan I . (1988). Trends Pharmacol. Sci., 9, 54–58.

  • Hansen MF . (1991). Clin. Orthop., 270, 237–246.

  • Hiebert SW, Packham G, Strom DK, Haffner R, Oren M, Zambetti G and Cleveland JL . (1995). Mol. Cell. Biol., 15, 6864–6874.

  • Hsieh JK, Chan FSG, O'Connor DJ, Mittnacht S, Zhong S and Lu X . (1999). Mol. Cell., 3, 181–193.

  • Hsieh JK, Fredersdorf S, Kauzarides T, Martin K and Lu X . (1997). Genes Dev., 11, 1840–1852.

  • Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH and Kaelin Jr WG . (2000). Nature, 407, 645–648.

  • Johnson DG . (1995). Oncogene, 11, 1685–1692.

  • Johnson DG and Schneider-Broussard R . (1998). Front. Biosci., 3, d447–d448.

  • Kane SE, Pastan I and Gottesman MM . (1990). J. Bioenerg. Biomembr., 22, 593–618.

  • Kowalik TF, DeGregori J, Leone G, Jakoi L and Nevins JR . (1998). Cell. Growth Differ., 9, 113–118.

  • Lavia P and Jansen-Durr P . (1999). BioEssay, 21, 221–230.

  • Lin X, Dowjat WK and Costa M . (1994). Cancer Res., 54, 2751–2754.

  • Macaluso M, Cinti C, Russo G, Russo A and Giordano A . (2003). Oncogene 22, 3511–3517.

  • Miller CW, Aslo A, Won A, Tan M, Lampkin B and Koeffler HP . (1996). J. Cancer Res. Clin. Oncol., 122, 559–565.

  • Moroni MC, Hickman ES, Denchi LE, Caprara G, Colli E, Cecconi F, Muller H and Helin K . (2001). Nat. Cell. Biol., 3, 552–558.

  • Nguyen KT, Liu B, Ueda K, Gottesman MM, Pastan I and Chin KV . (1994). Oncol. Res., 6, 71–77.

  • Oda Y, Matsumoto Y, Harimaya K, Iwamoto Y and Tsuneyoshi M . (2000). Oncol. Rep., 7, 859–866.

  • Orlando V, Strutt H and Paro R . (1997). Methods, 11, 205–214.

  • Park DJ, Nakamura H, Chumakov AM, Said JW, Miller CW, Chen DL and Koeffler HP . (1994). Oncogene, 9, 1899–1906.

  • Pucci B, Claudio PP, Masciullo V, Bellincampi L, Terrinoni A, Khalili K, Melino G and Giordano A . (2002). Oncogene, 21, 5897–5905.

  • Rayman JB, Takahashi Y, Indjeian VB, Dannenberg JH, Catchpole S, Watson RJ, Riele H and Dynlacht BD . (2002). Gen. Dev., 16, 933–947.

  • Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA and Dynlacht BD . (2002). Gen. Dev., 16, 245–256.

  • Seelan RS, Irwin M, van der Stoop P, Qian C, Kaelin Jr WG and Liu W . (2002). Neoplasia., 4, 195–203.

  • Serra M, Scotlandi K, Manara MC, Maurici D, Lollini PL, De Giovanni C, Toffoli G and Baldini N . (1993). Anticancer Res., 13, 323–329.

  • Shnyder SD, Hayes AJ and Pringle J . (1998). Br. J. Cancer, 78, 757–759.

  • Sigal A and Rotter V . (2000). Cancer Res., 60, 6788–6793.

  • Somasundaram K and El-Deiry WS . (2000). Front. Biosci., 5, d424–d437.

  • Stiewe T and Putzer BM . (2000). Nat. Genet., 26, 464–469.

  • Strauss BE and Haas M . (1995). Biochem. Biophys. Res. Commun., 217, 333–340.

  • Strauss BE, Shivakumar C, Deb SP, Deb S and Haas M . (1995). Biochem. Biophys. Res. Commun., 217, 825–831.

  • Takahashi Y, Rayman JB and Dynlacht BD . (2000). Gen. Dev., 14, 804–816.

  • Thottassery JV, Zambetti GP, Arimori A, Shuetz EG and Shuetz JD . (1997). Proc. Natl. Acad. Sci. USA, 94, 11037–11042.

  • Vogelstein B, Lane D and Levine AJ . (2000). Nature, 408, 307–310.

  • Weinberg RA . (1995). Ann. NY Acad. Sci., 758, 331–338.

  • Zaika A, Irwin M, Sansome C and Moll UM . (2001). J. Biol. Chem., 276, 11310–11316.

  • Zini N, Trimarchi C, Claudio PP, Stiegler P, Marinelli F, Maltarello MC, La Sala D, De Falco G, Russo G, Ammirati G, Maraldi NM, Giordano A and Cinti C . (2001). J. Cell Physiol., 89, 34–44.

Download references

Acknowledgements

We are grateful to Dr Fiorenzo Marinelli for the helpful and constructive comments on the manuscript and Dr Massimo Riccio for helping in the acquisition of confocal laser scanning images. This work was supported by CNR grant, MURST-LAG-CO3 grant, Sbarro health Research Organization and NIH grants.

Author information

Authors and Affiliations

  1. ITOI-CNR, Unit of Bologna, c/o IOR, Bologna, 40136, Italy

    Dario La Sala & Caterina Cinti

  2. Institute of Pathologic Anatomy and Histology, University of Siena, Siena, 53100, Italy

    Dario La Sala

  3. Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, 19107, PA, USA

    Marcella Macaluso, Antonio Giordano & Caterina Cinti

  4. Institute of Neuroscience, CNR, 56100, Pisa, Italy

    Carmela Trimarchi

Authors
  1. Dario La Sala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcella Macaluso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carmela Trimarchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caterina Cinti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caterina Cinti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

La Sala, D., Macaluso, M., Trimarchi, C. et al. Triggering of p73-dependent apoptosis in osteosarcoma is under the control of E2Fs–pRb2/p130 complexes. Oncogene 22, 3518–3529 (2003). https://doi.org/10.1038/sj.onc.1206487

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206487

Keywords

This article is cited by

Search

Advanced search

Quick links