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. 2004 Jun 15;380(Pt 3):605–610. doi: 10.1042/BJ20040337

Alternative reading frame protein (ARF)-independent function of CARF (collaborator of ARF) involves its interactions with p53: evidence for a novel p53-activation pathway and its negative feedback control.

Md Kamrul Hasan 1, Tomoko Yaguchi 1, Yasumasu Minoda 1, Takashi Hirano 1, Kazunari Taira 1, Renu Wadhwa 1, Sunil C Kaul 1
PMCID: PMC1224239  PMID: 15109303

Abstract

CARF, a collaborator of ARF (alternative reading frame protein), was cloned as a novel ARF-binding protein from a yeast-interaction screen. It potentiated ARF-mediated p53 function, and also caused a moderate increase in p53 activity in the absence of ARF. We herein report the molecular mechanism of ARF-independent function of CARF. By employing a variety of approaches, including overexpression of CARF, its suppression by small interfering RNA and use of protease inhibitors, we demonstrate that: (i) CARF directly interacts with wild-type p53, causing its stabilization and functional activation; and (ii) CARF and p53 levels show an inverse relationship that is instigated by a negative-feedback control via a proteasome-mediated degradation pathway.

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Selected References

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  1. Ashcroft M., Vousden K. H. Regulation of p53 stability. Oncogene. 1999 Dec 13;18(53):7637–7643. doi: 10.1038/sj.onc.1203012. [DOI] [PubMed] [Google Scholar]
  2. Bringold F., Serrano M. Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol. 2000 May;35(3):317–329. doi: 10.1016/s0531-5565(00)00083-8. [DOI] [PubMed] [Google Scholar]
  3. Dimri G. P., Itahana K., Acosta M., Campisi J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol. 2000 Jan;20(1):273–285. doi: 10.1128/mcb.20.1.273-285.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Fulci G., Labuhn M., Maier D., Lachat Y., Hausmann O., Hegi M. E., Janzer R. C., Merlo A., Van Meir E. G. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene. 2000 Aug 3;19(33):3816–3822. doi: 10.1038/sj.onc.1203700. [DOI] [PubMed] [Google Scholar]
  5. Hasan Md Kamrul, Yaguchi Tomoko, Sugihara Takashi, Kumar Penmetcha K. R., Taira Kazunari, Reddel Roger R., Kaul Sunil C., Wadhwa Renu. CARF is a novel protein that cooperates with mouse p19ARF (human p14ARF) in activating p53. J Biol Chem. 2002 Aug 1;277(40):37765–37770. doi: 10.1074/jbc.M204177200. [DOI] [PubMed] [Google Scholar]
  6. Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997 May 15;387(6630):296–299. doi: 10.1038/387296a0. [DOI] [PubMed] [Google Scholar]
  7. Honda R., Yasuda H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 1999 Jan 4;18(1):22–27. doi: 10.1093/emboj/18.1.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Jacobs J. J., Kieboom K., Marino S., DePinho R. A., van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999 Jan 14;397(6715):164–168. doi: 10.1038/16476. [DOI] [PubMed] [Google Scholar]
  9. James M. C., Peters G. Alternative product of the p16/CKDN2A locus connects the Rb and p53 tumor suppressors. Prog Cell Cycle Res. 2000;4:71–81. doi: 10.1007/978-1-4615-4253-7_7. [DOI] [PubMed] [Google Scholar]
  10. Kamijo T., Zindy F., Roussel M. F., Quelle D. E., Downing J. R., Ashmun R. A., Grosveld G., Sherr C. J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997 Nov 28;91(5):649–659. doi: 10.1016/s0092-8674(00)80452-3. [DOI] [PubMed] [Google Scholar]
  11. Korgaonkar Chandrashekhar, Zhao Lili, Modestou Modestos, Quelle Dawn E. ARF function does not require p53 stabilization or Mdm2 relocalization. Mol Cell Biol. 2002 Jan;22(1):196–206. doi: 10.1128/MCB.22.1.196-206.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Levine A. J. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323–331. doi: 10.1016/s0092-8674(00)81871-1. [DOI] [PubMed] [Google Scholar]
  13. Llanos S., Clark P. A., Rowe J., Peters G. Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nat Cell Biol. 2001 May;3(5):445–452. doi: 10.1038/35074506. [DOI] [PubMed] [Google Scholar]
  14. Lowe Scott W., Sherr Charles J. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev. 2003 Feb;13(1):77–83. doi: 10.1016/s0959-437x(02)00013-8. [DOI] [PubMed] [Google Scholar]
  15. Rowland Benjamin D., Denissov Serguei G., Douma Sirith, Stunnenberg Hendrik G., Bernards René, Peeper Daniel S. E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest. Cancer Cell. 2002 Jul;2(1):55–65. doi: 10.1016/s1535-6108(02)00085-5. [DOI] [PubMed] [Google Scholar]
  16. Serrano M. The tumor suppressor protein p16INK4a. Exp Cell Res. 1997 Nov 25;237(1):7–13. doi: 10.1006/excr.1997.3824. [DOI] [PubMed] [Google Scholar]
  17. Stott F. J., Bates S., James M. C., McConnell B. B., Starborg M., Brookes S., Palmero I., Ryan K., Hara E., Vousden K. H. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998 Sep 1;17(17):5001–5014. doi: 10.1093/emboj/17.17.5001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wadhwa R., Sugihara T., Taira K., Kaul S. C. The ARF-p53 senescence pathway in mouse and human cells. Histol Histopathol. 2004 Jan;19(1):311–316. doi: 10.14670/HH-19.311. [DOI] [PubMed] [Google Scholar]
  19. Wadhwa Renu, Sugihara Takashi, Hasan Md Kamrul, Duncan Emma L., Taira Kazunari, Kaul Sunil C. A novel putative collaborator of p19ARF. Exp Gerontol. 2003 Mar;38(3):245–252. doi: 10.1016/s0531-5565(02)00180-8. [DOI] [PubMed] [Google Scholar]
  20. Weber J. D., Jeffers J. R., Rehg J. E., Randle D. H., Lozano G., Roussel M. F., Sherr C. J., Zambetti G. P. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000 Sep 15;14(18):2358–2365. doi: 10.1101/gad.827300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Zhang Y., Xiong Y. Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth Differ. 2001 Apr;12(4):175–186. [PubMed] [Google Scholar]

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