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Vol. 12, Issue 2, 407-419, February 2001

Peroxide Sensors for the Fission Yeast Stress-activated Mitogen-activated Protein Kinase Pathway

Vicky Buck,^* Janet Quinn,^* Teresa Soto Pino,^* Humberto Martin, Jose Saldanha,^§ Kozo Makino,^* Brian A. Morgan,^¶ and Jonathan B.A. Millar^*¶

 Division of Yeast Genetics and  ^§Protein Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA United Kingdom; and  School of Biochemistry and Genetics, University of Newcastle-upon-Tyne, Tyne and Wear, NE2 4HH United Kingdom

The Schizosaccharomyces pombe stress-activated Sty1p/Spc1p mitogen-activated protein (MAP) kinase regulates gene expression through the Atf1p and Pap1p transcription factors, homologs of human ATF2 and c-Jun, respectively. Mcs4p, a response regulator protein, acts upstream of Sty1p by binding the Wak1p/Wis4p MAP kinase kinase kinase. We show that phosphorylation of Mcs4p on a conserved aspartic acid residue is required for activation of Sty1p only in response to peroxide stress. Mcs4p acts in a conserved phospho-relay system initiated by two PAS/PAC domain-containing histidine kinases, Mak2p and Mak3p. In the absence of Mak2p or Mak3p, Sty1p fails to phosphorylate the Atf1p transcription factor or induce Atf1p-dependent gene expression. As a consequence, cells lacking Mak2p and Mak3p are sensitive to peroxide attack in the absence of Prr1p, a distinct response regulator protein that functions in association with Pap1p. The Mak1p histidine kinase, which also contains PAS/PAC repeats, does not regulate Sty1p or Atf1p but is partially required for Pap1p- and Prr1p-dependent transcription. We conclude that the transcriptional response to free radical attack is initiated by at least two distinct phospho-relay pathways in fission yeast.

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^* These authors contributed equally to this work.

Permanent address: Department of Molecular Microbiology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka Suita, Osaka 565, Japan.

^¶ Corresponding authors. E-mail addresses: jmillar{at}nimr.mrc.ac.uk and B.A.Morgan{at}newcastle.ac.uk.

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Molecular Biology of the Cell
Vol. 12, 407-419, February 2001
Copyright © 2001 by The American Society for Cell Biology

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