Cell-cycle control linked to extracellular environment by MAP kinase pathway in fission yeast

Abstract

In fission yeast the onset of mitosis is brought about by Cdc2/Cdc13 kinase, which is inhibited by the Wee1/Mik1 tyrosine kinases and activated by Cdc25 tyrosine phosphatase. This control network integrates many signals, including those that monitor DNA replication, DNA damage and cell size. We report here that a fission yeast MAP kinase pathway links the cell-cycle G2/M control with changes in the extracellular environment that affect cell physiology. Fission yeast spc1- mutants have a G2 delay that is greatly exacerbated by growth in high osmolarity media and nutrient limitation. A lethal interaction of spc1 and cdc25 mutations shows that Spc1 promotes the onset of mitosis. Spc1 is a MAP kinase homologue that is activated by Wis1 kinase in response to osmotic stress and nutrient limitation. Spc1 is inactivated by Pyp1, a phosphatase previously identified as a mitotic inhibitor. Pyp1 dephosphorylates only tyrosine-173 of Spc1, unlike the dual-specificity phosphatases that have been shown to regulate other MAP kinases.

The Peroxiredoxin Repair Proteins

“…Pap1 is an AP-1-like transcription factor that under normal conditions associates with the nuclear export factor Crm1 in the cytoplasm (Toone et al, 1998). Sty1 is a mitogen-activated protein kinase (MAPK) that is known to phosphorylate the transcription factor Atf1 (Shiozaki et al, 1995;Degols et al, 1996;Shiozaki et al, 1996;Wilkinson et al, 1996). Under stress conditions with low levels of H 2 O 2 , Pap1 is activated by the formation of an intramolecular disulfide bond that prevents association with Crm1 and results in the nuclear accumulation (Toone et al, 1998;Kudo et al, 1999;Castillo et al, 2002;Quinn et al, 2002).…”

Stress‐activated signalling pathways in yeast

“…Disruption of sty1 þ and wis1 þ results in a plethora of phenotypes all of which are related to the response of the cells to different stress conditions. Thus, sty1 ¹ cells are sensitive to osmotic, oxidative and heat stress, DNA damaging agents such as UV irradiation and cisplatin and to treatment with multiple drugs and heavy metals (Millar et al 1995;Shiozaki & Russell 1995;Kato et al 1996;Degols & Russell 1997;Toone et al 1998); in addition, they are deficient in initiating and progressing down the sexual differentiation pathway which results in spore formation and rapidly lose viability when the stationary phase is reached (Millar et al 1995;Shiozaki & Russell 1995;Kato et al 1996). These latter two phenotypes also reflect defects in stress response-in this case stress that arises from nutrient depletion.…”

“…1). Within the core MAPK module, conservation is extensive; for example, the S. cerevisiae HOG1 and S. pombe Sty1 (also known as Spc1 and Phh1) kinases are Ϸ 50% identical to the mammalian p38 kinase (Brewster et al 1993;Lee et al 1994;Millar et al 1995;Shiozaki & Russell 1995;Kato et al 1996). This degree of conservation also extends to upstream components of the module.…”

Activation of Srk1 by the Mitogen-activated Protein Kinase Sty1/Spc1 Precedes Its Dissociation from the Kinase and Signals Its Degradation

“…sty1/spc1 mutants have a G2 delay that is greatly exacerbated by growth in high osmolarity. In addition, a lethal interaction of spc1/sty1 and cdc25 mutations shows that Spc1/Sty1 promotes the onset of mitosis (Shiozaki and Russell, 1995).…”

“…Several of the SAPK pathway components were isolated in screenings designed to identify new genes regulating cell cycle division (Millar et al, 1995;Shiozaki and Russell, 1995;Shiozaki et al, 1997), signifying the link between environmental stress response and cell cycle control. In S. pombe spc1/sty1 mutants were identified in two different genetic analyses, spc1 mutant as a recessive suppressor of lethality caused by loss of phosphatase 2C (Shiozaki and Russell, 1995) and sty1 mutant as a recessive suppressor of lethality caused by the simultaneous inactivation of pyp1 and pyp2 phosphatases (Millar et al, 1995). sty1/spc1 mutants have a G2 delay that is greatly exacerbated by growth in high osmolarity.…”