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:

Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases

Oncogene volume 18, pages 1093–1102 (1999)Cite this article

Abstract

Phosphorylation of the carboxyl-terminal domain (CTD) of RNA polymerase II is important for basal transcriptional processes in vivo and for cell viability. Several kinases, including certain cyclin-dependent kinases, can phosphorylate this substrate in vitro. It has been proposed that differential CTD phosphorylation by different kinases may regulate distinct transcriptional processes. We have found that two of these kinases, cyclin C/CDK8 and cyclin H/CDK7/p36, can specifically phosphorylate distinct residues in recombinant CTD substrates. This difference in specificity may be largely due to their varying ability to phosphorylate lysine-substituted heptapeptide repeats within the CTD, since they phosphorylate the same residue in CTD consensus heptapeptide repeats. Furthermore, this substrate specificity is reflected in vivo where cyclin C/CDK8 and cyclin H/CDK7/p36 can differentially phosphorylate an endogenous RNA polymerase II substrate. Several small-molecule kinase inhibitors have different specificities for these related kinases, indicating that these enzymes have diverse active-site conformations. These results suggest that cyclin C/CDK8 and cyclin H/CDK7/p36 are physically distinct enzymes that may have unique roles in transcriptional regulation mediated by their phosphorylation of specific sites on RNA polymerase II.

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

Similar content being viewed by others

References

  • Abraham RT, Acquarone M, Andersen A, Asensi A, Belle R, Berger F, Bergounioux C, Brunn G, Buquet-Fagot C, Fagot D, Glab N, Goudeau H, Goudeau M, Guerrier P, Houghton P, Hendriks H, Kloareg B, Lippai M, Marie D, Maro B, Meijer L, Mester J, Mulner-Lorillon O, Poulet SA, Schierenberg E, Schutte B, Vaulot D and Verlhac MH. . 1995 Biol. Cell 83: 105–120.

  • Akoulitchev S, Mäkelä TP, Weinberg RA and Reinberg D. . 1995 Nature 377: 557–560.

  • Allison LA, Moyle M, Shales M and Ingles CJ. . 1985 Cell 42: 599–610.

  • Allison LA, Wong JK-C, Fitzpatrick VD, Moyle M and Ingles CJ. . 1988 Mol. Cell. Biol. 8: 321–329.

  • Arias JA, Peterson SR and Dynan WS. . 1991 J. Biol. Chem. 266: 8055–8061.

  • Bartolomei MS, Halden NF, Cullen CR and Corden JL. . 1988 Mol. Cell. Biol. 8: 330–339.

  • Baskaran R, Chiang GG, Mysliwiec T, Kruh GD and Wang JYJ. . 1997 J. Biol. Chem. 272: 18905–18909.

  • Baskaran R, Dahmus ME and Wang JY. . 1993 Proc. Natl. Acad. Sci. USA 90: 11167–11171.

  • Bellier S, Dubois MF, Nishida E, Almouzni G and Bensaude O. . 1997 Mol. Cell. Biol. 17: 1434–1440.

  • Bregman DB, Du L, van der Zee S and Warren SL. . 1995 J. Cell Biol. 129: 287–298.

  • Cadena DL and Dahmus ME. . 1987 J. Biol. Chem. 262: 12468–12474.

  • Cagas PM and Corden JL. . 1995 Proteins 21: 149160.

  • Chambers RS and Dahmus ME. . 1994 J. Biol. Chem. 269: 26243–26248.

  • Chapman AB and Agabian N. . 1994 J. Biol. Chem. 269: 4754–4760.

  • Cisek LJ and Corden JL. . 1989 Nature 339: 679–684.

  • Cisek LJ and Corden JL. . 1991 Methods Enz. 200: 301–325.

  • Cismowski MJ, Laff GM, Solomon MJ and Reed SI. . 1995 Mol. Cell. Biol. 15: 2983–2992.

  • Cleveland DW, Fischer SG, Kirschner MW and Laemmli UK. . 1977 J. Biol. Chem. 252: 1102–1106.

  • Corden JL. . 1993 Curr. Opin. Genet. Dev. 3: 213–218.

  • Corden JL, Cadena DL, Ahearn Jr JM and Dahmus ME. . 1985 Proc. Natl. Acad. Sci. USA 82: 7934–7938.

  • Dahmus ME. . 1981 J. Biol. Chem. 256: 3332–3339.

  • Dahmus ME. . 1996 J. Biol. Chem. 271: 1900919012.

  • Du L and Warren SL. . 1997 J. Cell Biol. 136: 5–18.

  • Dubois M-F, Nguyen VT, Bellier S and Bensaude O. . 1994a J. Biol. Chem. 269: 13331–13336.

  • Dubois M-F, Nguyen VT, Dahmus ME, Pagès, G., Pouysségur J and Bensaude O. . 1994b EMBO J. 13: 4787–4797.

  • Dubois M-F, Vincent M, Vigneron M, Adamczewski J, Egly J-M and Bensaude O. . 1997 Nucleic Acids Res. 25: 694–700.

  • Edwards MC, Wong C and Elledge SJ. . 1998 Mol. Cell. Biol. 18: 4291–4300.

  • Feaver WJ, Gileadi O, Li Y and Kornberg RD. . 1991 Cell 67: 1223–1230.

  • Feaver WJ, Svejstrup JQ, Henry NL and Kornberg RD. . 1994 Cell 79: 1103–1109.

  • Field J, Nikawa J-I, Broek D, MacDonald B, Rodgers L, Wilson IA, Lerner RA and Wigler M. . 1988 Mol. Cell. Biol. 8: 2159–2165.

  • Gebara MM, Sayre MH and Corden JL. . 1997 J. Cell. Biochem. 64: 390–402.

  • Giesecke H, Barale JC, Langsley G and Cornelissen AW. . 1991 Biochem. Biophys. Res. Commun. 180: 1350–1355.

  • Glab N, Labidi B, Qin LX, Trehin C, Bergounioux C and Meijer L. . 1994 FEBS Lett. 353: 207–211.

  • Gruenwald S and Heitz J. . 1993 Baculovirus Expression Vector System: Procedures & Methods Manual, 2nd edn. PharMingen, San Diego.

    Google Scholar 

  • Grussenmeyer T, Scheidtmann KH, Hutchinson MA, Eckhart W and Walter G. . 1985 Proc. Natl. Acad. Sci. USA 82: 7952–7954.

  • Jiang Y and Gralla JD. . 1994 Nucleic Acids Res. 22: 4958–4962.

  • Kim E, Du L, Bregman DB and Warren SL. . 1997 J. Cell Biol. 136: 19–28.

  • Kuchin S, Yeghiayan P and Carlson M. . 1995 Proc. Natl. Acad. Sci. USA 92: 4006–4010.

  • Lee JM and Greenleaf AL. . 1989 Proc. Natl. Acad. Sci. USA 86: 3624–3628.

  • Lee JM and Greenleaf AL. . 1991 Gene Expr. 1: 149–167.

  • Lee JM and Grenleaf AL. . 1997 J. Biol. Chem. 272: 10990–10993.

  • Liao SM, Zhang J, Jeffery DA, Koleske AJ, Thompson CM, Chao DM, Viljoen M, van Vuuren HJ and Young RA. . 1995 Nature 374: 193–196.

  • Losiewicz MD, Carlson BA, Kaur G, Sausville EA and Worland PJ. . 1994 Biochem. Biophys. Res. Commun. 201: 589–595.

  • Lu H, Zawel L, Fisher L, Egly J-M and Reinberg D. . 1992 Nature 358: 641–645.

  • Mäkelä TP, Parvin JD, Kim J, Huber LJ, Sharp PA and Weinberg RA. . 1995 Proc. Natl. Acad. Sci. USA 92: 5174–5178.

  • Maldonado E, Shiekhattar R, Sheldon M, Cho H, Drapkin R, Rickert P, Lees E, Anderson CW, Linn S and Reinberg D. . 1996 Nature 381: 86–89.

  • Marshall NF, Peng J, Xie Z and Price DH. . 1996 J. Biol. Chem. 271: 27176–27183.

  • Marshall NF and Price DH. . 1995 J. Biol. Chem. 270: 12335–12338.

  • McCracken S, Fong N, Yankulov K, Ballantyne S, Pan G, Greenblatt J, Patterson SD, Wickens M and Bentley DL. . 1997 Nature 387: 357–361.

  • Meijer L. . 1996 Trends Cell Biol. 6: 393–397.

  • Misteli T and Warren G. . 1995 J. Cell Sci. 108: 2715–2727.

  • Mortillaro MJ, Blencowe BJ, Wei X, Nakayasu H, Du L, Warren SL, Sharp PA and Berezney R. . 1996 Proc. Natl. Acad. Sci. USA 93: 8253–8257.

  • Nonet M, Sweetser D and Young RA. . 1987 Cell 50: 909–915.

  • O'Brien T, Hardin S, Greenleaf A and Lis JT. . 1994 Nature 370: 75–77.

  • Payne JM and Dahmus ME. . 1993 J. Biol. Chem. 268: 80–87.

  • Peng J, Zhu Y, Milton JT and Price DH. . 1998 Genes Dev. 12: 755–762.

  • Rice SA, Long MC, Lam V and Spencer CA. . 1994 J. Virol. 68: 988–1001.

  • Rickert P. . 1997 Functional and Biochemical Characterization of the cyclin C/CDK8 kinase. PhD Thesis. Stanford University, California.

    Google Scholar 

  • Rickert P, Seghezzi W, Shanahan F, Cho H and Lees E. . 1996 Oncogene 12: 2631–2640.

  • Roy R, Adamczewski JP, Seroz T, Vermeulen W, Tasan J-P, Schaeffer L, Nigg EA, Joeijmakers JHJ and Egly J-M. . 1994 Cell 79: 1093–1101.

  • Sambrook J, Fritsch EF and Maniatis T. . Molecular Cloniong: A Laboratory Manual, 2nd edn. Cold Spring Harbor Laboratory Press, Plainview, NY.

  • Schulze-Gahmen U, Brandsen J, Jones JH, Morgan DO, Meijer L, Vesely J and Kim S-H. . 1995 Proteins 22: 378–391.

  • Sehgal PB, Darnell Jr JE and Tamm I. . 1976 Cell 9: 473–480.

  • Serizawa H, Conaway JW and Conaway RC. . 1993a Nature 363: 371–374.

  • Serizawa H, Conaway RC and Conaway JW. . 1993b J. Biol. Chem. 268: 17300–17308.

  • Serizawa H, Mäkelä TP, Conaway JW, Conaway RC, Weinberg RA and Young RA. . 1995 Nature 374: 280–282.

  • Shiekhattar R, Mermelstein F, Fisher RP, Drapkin R, Dynlacht B, Wessling HC, Morgan DO and Reinberg D. . 1995 Nature 374: 283–287.

  • Shilatifard A, Conaway JW and Conaway RC. . 1997 Curr. Opin. Genet. Dev. 7: 199–204.

  • Simon M, Séraphin B and Faye G. . 1986 EMBO J. 5: 2697–2701.

  • Song CZ. . 1996 Biochem. Biophys. Res. Commun. 229: 810–816.

  • Songyang Z, Blechner S, Hoagland N, Hoekstra MF, Piwnica-Worms H and Cantley LC. . 1994 Curr. Biol. 4: 973–982.

  • Steinmetz EJ. . 1997 Cell 89: 491–494.

  • Stevens A and Maupin MK. . 1989 Biochem. Biophys. Res. Commun. 159: 508–515.

  • Valay JG, Simon M and Faye G. . 1993 J. Mol. Biol. 234: 307–310.

  • Venetianer A, Dubois MF, Nguyen VT, Bellier S, Seo SJ and Bensaude O. . 1995 Eur. J. Biochem. 233: 83–92.

  • Vesley J, Havlicek L, Strnad M, Blow JJ, Donella-Deana A, Pinna L, Letham DS, Kato J-Y, Detivaud L, Leclerc S and Meijer L. . 1994 Eur. J. Biochem. 224: 771–786.

  • Wei P, Garber ME, Fang SM, Fischer WH and Jones KA. . 1998 Cell 92: 451–462.

  • West ML and Corden JL. . 1995 Genetics 140: 1223–1233.

  • Yankulov K, Yamashita K, Roy R, Egly JM and Bentley DL. . 1995 J. Biol. Chem. 270: 23922–23925.

  • Yuryev A and Corden JL. . 1996 Genetics 143: 661–671.

  • Yuryev A, Patturajan M, Litingtung Y, Joshi RV, Gentile C, Gebara M and Corden JL. . 1996 Proc. Natl. Acad. Sci. USA 93: 6975–6980.

  • Zehring WA, Lee JM, Weeks JR, Jokerst RS and Greenleaf AL. . 1988 Proc. Natl. Acad. Sci. USA 85: 3698–3702.

  • Zhu Y, Pe'ery T, Peng J, Ramanathan Y, Marshall N, Marshall T, Amendt B, Mathews MB and Price DH. . 1997 Genes Dev. 11: 2622–2632.

Download references

Acknowledgements

We thank David Morgan for his generous gift of cyclin H, CDK7, and p36MAT1-expressing baculoviruses. We are also grateful to F Shanahan for assistance with tissue culture. We thank J Bolen, D Mahony, W Seghezzi, F Shanahan and N Solvason for critical comments on the manuscript and W Huestis for helpful advice. DNAX Research Institute of Molecular and Cellular Biology is supported by the Schering – Plough Corporation.

Author information

Authors and Affiliations

  1. Department of Cell Signaling, DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, 94304, California, USA

    Paula Rickert & Emma Lees

  2. Department of Chemistry, Stanford University, Stanford, 94305-5080, California, USA

    Paula Rickert

  3. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, 21209, Maryland, USA

    Jeffry L Corden

Authors
  1. Paula Rickert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffry L Corden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emma Lees
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rickert, P., Corden, J. & Lees, E. Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases. Oncogene 18, 1093–1102 (1999). https://doi.org/10.1038/sj.onc.1202399

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202399

Keywords

This article is cited by

Search

Advanced search

Quick links