MAPK mediated cell cycle regulation is associated with Cdc25 turnover in<i>S. pombe</i>after exposure to genotoxic stress

Sundaram, Geetanjali; Palchaudhuri, Santanu; Dixit, Swati; Chattopadhyay, Dhrubajyoti

doi:10.4161/cc.7.3.5266

Cited by 9 publications

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“…Spc1 and Cdc25 have been shown to have a synthetic lethal interaction (11). There is evidence for the MAPK pathway being involved in Cdc25 regulation, spindle orientation checkpoint activation, and chromosome segregation (6,(12)(13)(14). Clearly, multiple layers of cross talk exist between the MAPK pathway and the factors controlling cell division in S. pombe.…”

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confidence: 99%

The Basic Leucine Zipper Domain Transcription Factor Atf1 Directly Controls Cdc13 Expression and Regulates Mitotic Entry Independently of Wee1 and Cdc25 in Schizosaccharomyces pombe

et al. 2014

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Progression into mitosis is a major point of regulation in the Schizosaccharomyces pombe cell cycle, and its proper control is essential for maintenance of genomic stability. Investigation of the G 2 /M progression event in S. pombe has revealed the existence of a complex regulatory process that is responsible for making the decision to enter mitosis. Newer aspects of this regulation are still being revealed. In this paper, we report the discovery of a novel mode of regulation of G 2 /M progression in S. pombe. We show that the mitogen-activated protein kinase (MAPK)-regulated transcription factor Atf1 is a regulator of Cdc13 (mitotic cyclin) transcription and is therefore a prominent player in the regulation of mitosis in S. pombe. We have used genetic approaches to study the effect of overexpression or deletion of Atf1 on the cell length and G 2 /M progression of S. pombe cells. Our results clearly show that Atf1 overexpression accelerates mitosis, leading to an accumulation of cells with shorter lengths. The previously known major regulators of entry into mitosis are the Cdc25 phosphatase and the Wee1 kinase, which modulate cyclin-dependent kinase (CDK) activity. The significantly striking aspect of our discovery is that Atf1-mediated G 2 /M progression is independent of both Cdc25 and Wee1. We have shown that Atf1 binds to the Cdc13 promoter, leading to activation of Cdc13 expression. This leads to enhanced nuclear localization of CDK Cdc2, thereby promoting the G 2 /M transition. The mammalian basic leucine zipper domain (bZIP) family transcription factor ATF2 is known to be associated with multiple cellular processes, including stress responses, DNA damage responses, and cell cycle regulation. Schizosaccharomyces pombe has a well-characterized ATF2 homolog (Atf1) with functions similar to those of the human ATF2 protein (1-4). It is important for heterochromatin formation and meiotic recombination. Atf1 has also been shown to influence some very important events during S. pombe cell division. In S. pombe, Atf1 was first isolated as the suppressor of the ⌬spc1 phenotype (1). Spc1 is the major mitogenactivated protein kinase (MAPK) in S. pombe and is the homolog of mammalian p38MAPK. It has also been implicated at many important stages of cell cycle control in S. pombe. Atf1 is known to be associated with activation of the spindle orientation checkpoint (5) that controls the metaphase-to-anaphase transition and activation of the anaphase-promoting complex (APC) leading to mitotic exit. It has a synthetic lethal interaction with Cut1 (6). Atf1 is also necessary for accumulation of cells in G 1 after nitrogen starvation (1). It has been shown to be important for degradation of the mitotic cyclin Cdc13 by activating the APC/cyclosome (APC/C) ubiquitin ligase (7).The major point of regulation of the S. pombe cell cycle is the transition from G 2 phase into mitosis. This transition is dependent on the activity of the cyclin-dependent kinase (CDK) Cdc2. The known important regulators of Cdc2 activity in S. pombe a...

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The Basic Leucine Zipper Domain Transcription Factor Atf1 Directly Controls Cdc13 Expression and Regulates Mitotic Entry Independently of Wee1 and Cdc25 in Schizosaccharomyces pombe

et al. 2014

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“…The above results indicated that overexpression of Spc1 leads to a delay in mitotic initiation in S. pombe cells which is triggerred by a hyperactive Cdc2 and occurs via Cdc25 relocalization. Earlier studies have also implicated Spc1 to be associated with Cdc25 regulation in S. pombe (Sundaram et al, ). Cdc25 relocalization is known to be dependent on the activity of the 14–3–3 protein Rad24 (Lopez‐Girona, Furnari, Mondesert, & Russell, ; Zeng & Piwnica‐Worms, ).…”

Section: Resultsmentioning

confidence: 84%

“…It should be noted here that we found that the cells overexpressing Spc1 have higher levels of phosphorylated (active) Spc1 (Figure S1b) compared with the wis1DD mutant cells. Earlier studies with Spc1 have indicated that the levels of Spc1 in a cell dictate whether it acts as a mitotic inhibitor or accelerator (Hartmuth & Petersen, ; Petersen & Nurse, ; Sundaram et al, ). Our overexpression system, therefore, mimics the condition when Spc1 acts as a mitotic inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…The intriguing pattern that has emerged from distinct reports about its influence on mitosis is that Spc1 can have contrasting effects on mitotic entry decisions. A moderate increase in Spc1 activity promotes (Hartmuth & Petersen, ; Petersen & Nurse, ) mitotic entry (in response to nutrient stress) while a higher increase (Hartmuth & Petersen, ; Sundaram, Palchaudhuri, Dixit, & Chattopadhyay, ) leads to activation of the G2/M checkpoint (in response to oxidative, genotoxic or heat stress). In the former case its function resembles the role of mammalian ERK (Liu, Yan, Zhou, Terada, & Erikson, ; Wang et al, ), while in the latter case the functional similarity is with the mammalian p38 MAPK (Bulavin, Amundson, & Fornace, ; Bulavin et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…All that is known is that the Spc1‐dependent kinase Srk1 is involved in Cdc25 downregulation by promoting the interaction between Cdc25 and the 14–3–3 protein Rad24 (Lopez‐Aviles et al, ; Smith et al, ). Both Spc1 and its mammalian homologue p38 have been implicated in Cdc25 downregulation during genotoxic stress (Bulavin et al, ; Sundaram et al, ). However Srk1 is not known to be enhanced during the DNA damage checkpoint activation (Lopez‐Aviles et al, ; Smith et al, ).…”

Section: Introductionmentioning

confidence: 99%

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The fission yeast MAPK Spc1 senses perturbations in Cdc25 and Wee1 activities and targets Rad24 to restore this balance

Paul

Ghosal

Bandyopadhyay

et al. 2017

Yeast

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Mitogen-activated protein kinases (MAPKs) play vital roles in multiple cellular processes and represent prominently pursued targets for development of therapeutic regimes. The MAPK Spc1 (p38 homologue) is known to be very important for both mitotic promotion and delay in Schizosaccharomyces pombe. However, the mechanism responsible for mitotic inhibition has remained elusive. Cdc25 (Cdc2 activator) and Wee1 (Cdc2 inhibtor) are important determinants of mitotic timing in all eukaryotes. Our results show that Spc1 can sense the perturbations in the balance of Cdc25 and Wee1 activities in S. pombe and that its function as a mitotic inhibitor is very important for controlling the same. An Spc1-Srk1-Rad24-dependent pathway for mitotic inhibition has been reported earlier.Here we report the presence of an alternative mechanism wherein Spc1 targets the 14-3-3 protein, Rad24, independently of Srk1, leading to relocalization of Cdc25 and mitotic inhibition. Our observations suggest that this pathway can serve as a backup mechanism for Cdc2 inactivation in the absence of Wee1.

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MAPK mediated cell cycle regulation is associated with Cdc25 turnover inS. pombeafter exposure to genotoxic stress

Cited by 9 publications

References 36 publications

The Basic Leucine Zipper Domain Transcription Factor Atf1 Directly Controls Cdc13 Expression and Regulates Mitotic Entry Independently of Wee1 and Cdc25 in Schizosaccharomyces pombe

The Basic Leucine Zipper Domain Transcription Factor Atf1 Directly Controls Cdc13 Expression and Regulates Mitotic Entry Independently of Wee1 and Cdc25 in Schizosaccharomyces pombe

The fission yeast MAPK Spc1 senses perturbations in Cdc25 and Wee1 activities and targets Rad24 to restore this balance

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