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Vol. 18, Issue 12, 4794-4802, December 2007

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Atf1 Is a Target of the Mitogen-activated Protein Kinase Pmk1 and Regulates Cell Integrity in Fission Yeast

Hirofumi Takada^*, Masayuki Nishimura^*, Yuta Asayama^*, Yoshiaki Mannse^*, Shunji Ishiwata^*, Ayako Kita^*, Akira Doi^*, Aiko Nishida^*, Naoyuki Kai^*, Sayako Moriuchi^*, Hideki Tohda, Yuko Giga-Hama, Takayoshi Kuno, and Reiko Sugiura^*

*Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, 577-8502, Japan; Asahi Glass Schizosaccharomyces pombe Expression System Division, Research Center, Asahi Glass Co., Ltd., Yokohama, 221-8755, Japan; and Division of Molecular Pharmacology and Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

Submitted March 27, 2007; Revised August 24, 2007; Accepted September 10, 2007
Monitoring Editor: Charles Boone

In fission yeast, knockout of the calcineurin gene resulted in hypersensitivity to Cl^–, and the overexpression of pmp1⁺ encoding a dual-specificity phosphatase for Pmk1 mitogen-activated protein kinase (MAPK) or the knockout of the components of the Pmk1 pathway complemented the Cl^– hypersensitivity of calcineurin deletion. Here, we showed that the overexpression of ptc1⁺ and ptc3⁺, both encoding type 2C protein phosphatase (PP2C), previously known to inactivate the Wis1–Spc1–Atf1 stress-activated MAPK signaling pathway, suppressed the Cl^– hypersensitivity of calcineurin deletion. We also demonstrated that the mRNA levels of these two PP2Cs and pyp2⁺, another negative regulator of Spc1, are dependent on Pmk1. Notably, the deletion of Atf1, but not that of Spc1, displayed hypersensitivity to the cell wall-damaging agents and also suppressed the Cl^– hypersensitivity of calcineurin deletion, both of which are characteristic phenotypes shared by the mutation of the components of the Pmk1 MAPK pathway. Moreover, micafungin treatment induced Pmk1 hyperactivation that resulted in Atf1 hyperphosphorylation. Together, our results suggest that PP2C is involved in a negative feedback loop of the Pmk1 signaling, and results also demonstrate that Atf1 is a key component of the cell integrity signaling downstream of Pmk1 MAPK.

Address correspondence to: Reiko Sugiura (sugiurar{at}phar.kindai.ac.jp).