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Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1

Oncogene volume 18, pages 1033–1040 (1999)Cite this article

Abstract

The DNA repair protein apurinic endonuclease (APE/Ref-1) exerts several physiological functions such as cleavage of apurinic/apyrimidinic sites and redox regulation of the transcription factor AP-1, whose activation is part of the cellular response to DNA damaging treatments. Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1. Inhibition of CKII mediated phosphorylation of APE/Ref-1 blocked mutagen-stimulated increase in AP-1 binding. It also abrogated the induction of c-Jun protein and rendered cells more sensitive to induced DNA damage. Thus, phosphorylation of APE/Ref-1 appears to be involved in regulating the different physiological activities of the enzyme. CKII mediated phosphorylation of APE/Ref-1 and concomitant increase in AP-1 binding activity appears to be a novel mechanism of cellular stress response, forcing transcription of AP-1 target gene(s) the product(s) of which may exert protective function.

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Abbreviations

AP-1:

activator protein 1

APE/Ref-1:

apurinic/apyrimidinic endonuclease/redox factor 1

CKI:

casein kinase I

CKII:

casein kinase II

MMS:

methyl methanesulfonate

PKA:

protein kinase A

SDS:

sodium dodecylsulfate.

References

  • Abate C, Patel L, Rauscher III FJ and Curran T. . 1990 Science 249: 1157–1160.

  • Ackerman P, Glover CV and Osheroff N. . 1990 Proc. Natl. Acad. Sci. USA 87: 821–825.

  • Ackerman P, Glover CVC and Osheroff N. . 1985 Proc. Natl. Acad. Sci. USA 82: 3164–3168.

  • Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S-I, Itoh N, Shibuya M and Fukami Y. . 1987 J. Biol. Chem. 262: 5592–5595.

  • Barnes DE, Tomkinson AE, Lehman AR, Webster DB and Lindahl T. . 1992 Cell 69: 495–503.

  • Barzilay G, Walker LJ, Robson CN and Hickson ID. . 1995 Nucl. Acid Res. 23: 1544–1550.

  • Bradford MM. . 1976 Anal. Biochem. 72: 248–254.

  • Caizergues-Ferrer M, Belenguer P, Lapeyre B, Amalric F, Walace MO and Olson MOL. . 1987 Biochemistry 26: 7876–7883.

  • Cavigelli M. Dolfi F, Claret F-X and Karin M. . 1995 EMBO J. 14: 5957–5964.

  • Chen DS, Herman T and Demple B. . 1991 Nucl. Acid Res. 19: 5907–5914.

  • Chiu R, Boyle WJ, Meek J, Smeal T, Hunter T and Karin M. . 1988 Cell 54: 541–552.

  • Cochet C, Feige JJ, Pirollet F, Keramidas M and Chambaz EM. . 1982 Biochem. Pharmacol. 31: 1357–1361.

  • Deng T and Karin M. . 1994 Nature 371: 171–175.

  • Devary Y, Gottlieb RA, Smeal T and Karin M. . 1992 Cell 71: 1081–1091.

  • Dosch J and Kaina B. . 1996 Oncogene 13: 1927–1935.

  • Duceman BW, Rose KM and Jacob ST. . 1981 J. Biol. Chem. 256: 10755–10758.

  • Durban E, Goodenough M, Mills J and Busch H. . 1985 EMBO J. 4: 2921–2926.

  • Ford JM and Hanawalt PC. . 1997 J. Biol. Chem. 272: 28073–28080.

  • Friedberg EC, Walker GC and Siede W. . 1995 DNA Repair and Mutagenesis. ASM Press, Washington.

    Google Scholar 

  • Grunicke H, Hofmann J, Utz I and Uberall F. . 1994 Ann. Hematol. 69: 1–6.

  • Gzuder SN, Sung P, Bailly V, Prakash L and Prakash S. . 1994 Nature 369: 578–581.

  • Haas S and Kaina B. . 1995 Carcinogenesis 16: 985–991.

  • Hagiwara M, Inoue S, Tanaka T, Nunoki K, Ito M and Hidaka H. . 1988 Biochem. Pharmacol. 37: 2987–2992.

  • Hathaway GM and Traugh JA. . 1982 Curr. Top. Cell Regul. 21: 101–127.

  • Issinger O-G, Martin T, Richter WW, Olson M and Fujiki H. . 1988 EMBO J. 7: 1621–1626.

  • Jayaraman L, Murthy KGK, Zhu C, Curran T, Xanthoudiakis S and Prives C. . 1997 Genes Dev. 11: 558–570.

  • Jones NJ, Ellard S, Waters R and Parry EM. . (1993). C arcinogenesis 14: 2487–2494.

  • Kaina B, Haas S and Kappes H. . 1997 Cancer Res. 57: 2721–2731.

  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J and Woodgett JR. . (1994). N ature 369: 156–160.

  • Lee S-L, Schweppe JS and Jungmann RA. . 1984 J. Biol. Chem. 259: 14695–14701.

  • Levin JD and Demple B. . 1990 Nucl. Acids Res. 18: 5069–5075.

  • Levine AJ. . 1997 Cell 88: 323–331.

  • Liebermann DA, Hoffman B and Steinman RA. . 1995 Oncogene 11: 199–210.

  • Luscher B, Christenson E, Litchfield DW, Krebs EG and Eisenman RN. . 1990 Nature 344: 517–522.

  • Matter WF, Brown RF and Vlahos CJ. . 1992 Biochem. Biophys. Res. Commun. 186: 624–631.

  • Minden A, Lin A, Claret F-X. Abo A and Karin M. . 1995 Cell 81: 1147–1157.

  • Okazaki T, Chung U, Nishishita T, Ebisu S, Usuda S, Mishiro S, Xanthoudakis S, Igarashi T and Ogata E. . 1994 J. Biol. Chem. 269: 27855–27862.

  • Prigent C, Lasko DD, Kodama K, Woodgett JR and Lindahl T. . 1992 Embo J. 11: 2925–2933.

  • Ritke MK, Murray NR, Allan WP, Fields AP and Yalowich JC. . 1995 Mol. Pharmacol. 48: 798–805.

  • Sachsenmaier C, Radler-Pohl A, Zinck R, Nordheim A, Herrlich P and Rahmsdorf HJ. . 1994 Cell 78: 963–972.

  • Sanchez I, Hughes RT, Mayer BJ, Yee K, Woodgett JR, Avruch J, Kyriakis JM and Zon LI. . 1994 Nature 372: 794–798.

  • Schneider HR, Reichert GH and Issinger O-G. . 1986 Eur. J. Biochem. 161: 733–738.

  • Schreiber M, Baumann B, Cotton M, Angel P and Wagner EF. . 1995 EMBO J. 14: 5338–5349.

  • Smith PJ and Makinson TA. . 1989 Cancer Res. 49: 1118–1124.

  • Sommercorn J and Krebs EG. . 1987 J. Biol. Chem. 262: 3839–3843.

  • Srivastava AK. . 1985 Biochem. Biophys. Res. Commun. 131: 1–5.

  • Stryer L. . 1998 Biochemistry W H Freeman and Company New York.

    Google Scholar 

  • Teitz T, Eli D, Penner M, Bakhanashvili M, Naiman T, Timme TL, Wood CM, Moses RE and Canaani D. . 1990 Mut. Res. 236: 85–97.

  • Tuteja N, Huang NW, Skopac D, Tuteja R, Hrvatic S, Zhang J, Pongor S, Joseph G, Faucher C and Amalric Fea. . 1995 Gene 160: 143–148.

  • van Dam H, Duyndam M, Rottier R, Bosch A, de Vries-Smits L, Herrlich P, Zantema A, Angel P and van-der-Eb AJ. . 1993 EMBO J. 12: 479–483.

  • van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P and Angel P. . 1995 EMBO J. 14: 1798–1811.

  • Vassetzky YS, Alghisi GC, Roberts E and Gaser SM. . 1996 Br. J. Cancer 73: 1201–1209.

  • Wada T, Takagi T, Yamaguchi Y, Kawase H, Hiramoto M, Ferdous S, Takayama M, Lee KA, Hurst HC and Handa H. . 1996 Nucl. Acid Res. 24: 876–884.

  • Walker LJ, Craig RB, Harris AL and Hickson ID. . 1994 Nucl. Acid Res. 22: 4884–4889.

  • Walker LJ, Robson CN, Black E, Gillespie D and Hickson ID. . 1993 Mol. Cell. Biol. 13: 5370–5376.

  • Wang CY, Mayo MW and Baldwin Jr AS. . 1996 Science 274: 784–786.

  • Wang XZ and Ron D. . 1996 Science 272: 1347–1349.

  • Weeda G, Van Ham RCA, Vermeulen W, Bootsma D, Van Der Eb AJ and Hoeijmakers JHJ. . 1990 Cell 62: 777–791.

  • Xanthoudakis S, Miao G, Wang F, Pan Y-CE and Curran T. . 1992 EMBO J. 11: 3323–3335.

  • Yao K-S, Xanthoudakis S, Curran T and O'Dwyer PJ. . 1994 Mol. Cell. Biol. 14: 5997–6003.

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Acknowledgements

We would like to thank Dr OG Issinger (Odense, Denmark) for generously providing the protein kinases CKII and CKI. Furthermore we would like to thank Dr Nastaincyk (Homburg, Germany) for his gift of the catalytic subunit of PKA, Dr S Mitra for APE cDNA, and C Kost for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (Fr 1241/1-1 and SFB 519, B4) and the NMFZ Mainz.

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  1. Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, Mainz, D-55131, Germany

    Gerhard Fritz & Bernd Kaina

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Fritz, G., Kaina, B. Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1. Oncogene 18, 1033–1040 (1999). https://doi.org/10.1038/sj.onc.1202394

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