Abstract
The proteins of the retinoblastoma family are potent inhibitors of cell cycle progression. It is well documented that their growth-inhibitory activity can be abolished by phosphorylation on serine and threonine residues by cyclin dependent kinases. In contrast, very little is known about the dephosphorylation of retinoblastoma-family proteins. We report here the isolation, by virtue of its ability to associate with p107, of a novel Protein Phosphatase 2A (PP2A) regulatory subunit, named PR59. PR59 shares sequence homology with a known regulatory subunit of PP2A, PR72, but differs from PR72 in its expression pattern and its functional properties. We show that PR59 co-immunoprecipitates with the PP2A catalytic subunit, indicating that PR59 is a genuine component of PP2A holo-enzymes. In vivo, PR59 associates specifically with p107, but not with pRb. Elevated expression of PR59 results in dephosphorylation of p107, but not of pRb, and inhibits cell proliferation by causing cells to accumulate in G1. These data support a model in which the distinct PP2A regulatory subunits act to target the PP2A catalytic subunit to specific substrates and suggest a role for PP2A in regulation of p107.
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References
Altiok S, Xu M and Spiegelman BM. . 1997 Genes & Dev. 11: 1987–1998.
Altschul SF, Gish W, Miller W, Myers EW and Lipman DJ. . 1990 J. Mol. Biol. 215: 403–410.
Beijersbergen RL and Bernards R. . 1996 Biochem. Biophys. Acta, Rev. Cancer. 1287: 103–120.
Beijersbergen RL, Carlée L, Kerkhoven RM and Bernards R. . 1995 Genes & Dev. 9: 1340–1353.
Beijersbergen RL, Kerkhoven RM, Zhu L, Carlee L, Voorhoeve PM and Bernards R. . 1994 Genes & Dev. 8: 2680–2690.
Bernards R. . 1997 Biochem. Biophys. Acta. Rev. Cancer 1333: M33–M40.
Cegielska A, Shaffer S, Derua R, Goris J and Virshup DM. . 1994 Mol. Cell. Biol. 14: 4616–4623.
Chevray PM and Natans D. . 1992 Proc. Nat. Acad. Sci. USA 89: 5789–5793.
Cohen P, Klumpp S and Schelling DL. . 1989 FEBS Lett. 250: 596–600.
Cohen PT, Brewis ND, Hughes V and Mann DJ. . 1990 FEBS Lett. 268: 355–359.
Dou QP, An B and Will PL. . 1995 Proc. Natl. Acad. Sci. USA 92: 9019–9023.
Dowdy FD, Hinds PW, Louie K, Reed SI and Weinberg RA. . 1993 Cell 73: 499–511.
Durfee T, Becherer K, Chen PL, Yeh SH, Yang Y, Kilburn AE, Lee WH and Elledge SJ. . 1993 Genes & Dev. 7: 555–569.
Dynlacht BD, Flores O, Lees JA and Harlow E. . 1994 Genes & Dev. 8: 1772–1786.
Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J and Livingston DM. . 1993 Cell 73: 487–497.
Favre B, Zolnierowicz S, Turowski P and Hemmings BA. . 1994 J. Biol. Chem. 269: 16331–16317.
Field J, Nikawa JI, Broek D, MacDonald B, Rodgers L, Wilson IA, Lerner RA and Wigler M. . 1988 Mol. Cell. Biol. 8: 2159–2165.
Hannon GJ, Demetrick D and Beach D. . 1993 Genes & Dev. 7: 2378–2391.
Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ. . 1993 Cell 75: 805–816.
Hemmings BA, Adams PC, Maurer F, Muller P, Goris J, Merlevede W, Hofsteenge J and Stone SR. . 1990 Biochemistry 29: 3166–3173.
Hendrix P, Mayer-Jackel RE, Cron P, Goris J, Hofsteenge J, Merlevede W and Hemmings BA. . 1993a J. Biol. Chem. 268: 15267–15276.
Hendrix P, Turowski P, Mayer JR, Goris J, Hofsteenge J, Merlevede W and Hemmings BA. . 1993b J. Biol. Chem. 268: 7330–7337.
Hijmans EM, Voorhoeve PM, Beijersbergen RL, van't Veer LJ and Bernards R. . 1995 Mol. Cell. Biol. 15: 3082–3089.
Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI and Weinberg RA. . 1992 Cell 70: 993–1006.
Honkanan RE, Codispoti BA, Tse K and Boynton AL. . 1994 Toxicon 32: 339–350.
Hubbard MJ and Cohen P. . 1993 Trends Biochem. Sci. 18: 172–177.
Kamibayashi C, Estes R, Lickteig RL, Yang SI, Craft C and Mumby MC. . 1994 J. Biol. Chem. 269: 20139–20148.
Kamibayashi C and Mumby MC. . 1995 Adv. Prot. Phosphatases 9: 195–210.
Kitagawa M, Higashi H, Suzuki TI, Segawa K, Hanks SK, Taya Y, Nishimura S and Okuyama A. . 1995 Oncogene 10: 229–236.
Kozak M. . 1992 Annu. Rev. Cell. Biol. 8: 197–225.
Krek W, Ewen ME, Shirodkar S, Arany Z, Kaelin Jr WG and Livingston DM. . 1994 Cell 78: 161–172.
Lees E, Faha B, Dulic V, Reed SI and Harlow E. . 1992 Genes & Dev. 6: 1874–1885.
Li LJ, Naeve GS and Lee AS. . 1993a Proc. Natl. Acad. Sci. USA 90: 3554–3558.
Li Y, Graham C, Lacy S, Duncan AMV and Whyte P. . 1993b Genes & Dev. 7: 2366–2377.
Mayer RE, Hendrix P, Cron P, Matthies R, Stone SR, Goris J, Merlevede W, Hofsteenge J and Hemmings BA. . 1991 Biochemistry 30: 3589–3597.
Mayer-Jaekel RE and Hemmings BA. . 1994 Trends Cell Biol. 4: 287–291.
McCright B and Virshup DM. . 1995 J. Biol. Chem. 270: 26123–26128.
Mumby MC and Walter G. . 1993 Physiol. Rev. 73: 673–699.
Nelson DA, Krucher NA and Ludlow JW. . 1997 J. Biol. Chem. 272: 4528–4535.
Nelson DA and Ludlow JW. . 1997 Oncogene 14: 2407–2415.
Okamoto K, Kamibayashi C, Serrano M, Prives C, Mumby MC and Beach D. . 1996 Mol. Cell. Biol. 16: 6593–6602.
Pallas DC, Weller W, Jaspers S, Miller TB, Lane WS and Roberts TM. . 1992 J. Virol. 66: 886–893.
Radulescu RT. . 1995 Med. Hypotheses 44: 28–31.
Schiestl RH and Gietz RD. . 1989 Curr. Genet. 16: 339–346.
Shirodkar S, Ewen M, DeCaprio JA, Morgan J, Livingston DM and Chittenden T. . 1992 Cell 68: 157–166.
Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M and Mumby MC. . 1993 Cell 75: 887–897.
Stone SR, Mayer R, Wernet W, Maurer F, Hofsteenge J and Hemmings BA. . 1988 Nucleic Acids Res. 16: 11365.
Tehrani MA, Mumby MC and Kamibayashi C. . 1996 J. Biol. Chem. 271: 5164–5170.
Tung HY, De RH, Zhao LJ, Cayla X, Roques BP and Ozon R. . 1997 FEBS Lett. 401: 197–201.
van den Heuvel S and Harlow E. . 1993 Science 262: 2050–2054.
Van der Eb AJ and Graham FL. . 1980 Meth. Enzymol. 65: 826–839.
Virshup DM, Cegielska A, Russo A, Kelly TJ and Shaffer S. . 1993 Adv. Prot. Phosphatases 7: 271–293.
Weinberg RA. . 1995 Cell 81: 323–330.
Xu M, Sheppard KA, Peng CY, Yee AS and Piwnica WH. . 1994 Mol. Cell. Biol. 14: 8420–8431.
Zhu L, Enders G, Lees JA, Beijersbergen RL, Bernards R and Harlow E. . 1995 EMBO J. 14: 1904–1913.
Zhu L, van den Heuvel S, Helin K, Fattaey A, Ewen M, Livingston D, Dyson N and Harlow E. . 1993 Genes & Dev. 7: 1111–1125.
Zolnierowicz S, Van HC, Andjelkovic N, Cron P, Stevens I, Merlevede W, Goris J and Hemmings BA. . 1996 Biochem. J. 317: 187–194
Acknowledgements
We thank Helen Brantjes for assistance, Natasja Andjelkovic and Dr Brian Hemmings for the kind gift of various plasmids and advice, Dr Ron Kerkhoven for providing RNA, Tony van Hamersfeld for assistance in generating PR59 antiserum and Daniel Peeper for critical reading of this manuscript. This work was supported by a grant from the Netherlands Organization for Scientific Research (NWO). The nucleotide sequence reported in this paper has been submitted to the Genbank database, and has been assigned accession number AF050165.
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Voorhoeve, P., Hijmans, E. & Bernards, R. Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein. Oncogene 18, 515–524 (1999). https://doi.org/10.1038/sj.onc.1202316
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DOI: https://doi.org/10.1038/sj.onc.1202316
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