Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation

Arsenault, Heather E.; Roy, Jagoree; Mapa, Claudine; Cyert, Martha S.; Benanti, Jennifer A.

doi:10.1091/mbc.e15-07-0469

Cited by 17 publications

(37 citation statements)

References 47 publications

(65 reference statements)

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“…These results are in agreement with a report that phosphorylation of the N-terminal region of Hcm1 promotes its degradation (16). Our MS analysis revealed many in vivo Hcm1 phosphorylation sites at different positions outside the N-terminal region, which includes some of the C-terminal phosphorylation sites suggested to regulate Hcm1 function (16,47). The positive regulatory phosphorylation of those sites is thought to be promoted during the cell cycle in a CDK-dependent manner (16,39).…”

Section: Discussionsupporting

confidence: 92%

“…Arsenault et al reported that environmental stresses dephosphorylate C-terminal phosphorylation sites through the Cnb1 calcium-activated phosphatase, thereby negatively regulating Hcm1 function, and suggested Hcm1 as a rheostat that controls cell proliferation (47). Our analyses indicated that N-terminal phosphorylation sites influence the cell wall stress response by negatively regulating Hcm1 protein level at the cell wall integrity checkpoint, suggesting a role for Hcm1 as a brake.…”

Section: Discussionmentioning

confidence: 51%

“…It is suggested that the positive function of Hcm1 regulated by C-terminal phosphorylation, at least in part, persists during the checkpoint, since, in the collective mutant used in this study, Hcm1 function was not abolished. Although, as shown previously, stress-inductive Cnb1 phosphatase activity contributes to the Hcm1 function in the cellular response to environmental stresses (47), there may be temporally or functionally different roles in the regulatory mechanisms, which should be revealed by further analysis of combinations of phosphosite mutations.…”

Section: Discussionmentioning

confidence: 75%

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The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint

Negishi

Veis

Hollenstein

et al. 2016

Molecular and Cellular Biology

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The cell wall integrity (CWI) checkpoint in the budding yeast Saccharomyces cerevisiae coordinates cell wall construction and cell cycle progression. In this study, we showed that the regulation of Hcm1, a late-S-phase transcription factor, arrests the cell cycle via the cell wall integrity checkpoint. Although the HCM1 mRNA level remained unaffected when the cell wall integrity checkpoint was induced, the protein level decreased. The overproduction of Hcm1 resulted in the failure of the cell wall integrity checkpoint. We identified 39 Hcm1 phosphorylation sites, including 26 novel sites, by tandem mass spectrometry analysis. A mutational analysis revealed that phosphorylation of Hcm1 at S61, S65, and S66 is required for the proper onset of the cell wall integrity checkpoint by regulating the timely decrease in its protein level. Hyperactivation of the CWI mitogen-activated protein kinase (MAPK) signaling pathway significantly reduced the Hcm1 protein level, and the deletion of CWI MAPK Slt2 resulted in a failure to decrease Hcm1 protein levels in response to stress, suggesting that phosphorylation is regulated by CWI MAPK. In conclusion, we suggest that Hcm1 is regulated negatively by the cell wall integrity checkpoint through timely phosphorylation and degradation under stress to properly control budding yeast proliferation. Critical events during cell cycle progression, such as DNA replication and mitosis, are regulated by cell cycle checkpoints to ensure the proper completion of cell division. The cell cycle in the budding yeast Saccharomyces cerevisiae is coordinated with bud growth to secure the morphological space for cell division (1). One of the cell cycle checkpoints required to monitor budding morphology is the morphogenesis checkpoint (2), and the other is the cell wall integrity (CWI) checkpoint (3). They function independently to coordinate bud growth and cell wall construction, respectively, with cell cycle progression (4). Without a supply of cell wall materials for bud growth, the budding yeast cell cycle is arrested before entry into M phase and cannot proceed to mitosis (3).Compared to the morphogenesis checkpoint that regulates Swe1 phosphorylation and its degradation to activate cyclin-dependent kinase (CDK) (5), the primary function of the cell wall integrity checkpoint is inhibiting cell cycle progression to mitosis, which is achieved essentially by downregulating M-phase cyclin CLB2 (3, 4). During functions of the active cell wall integrity checkpoint, cells accumulate at the small budded state. Budding starts as cells proceed to S phase; thus, the checkpoint must be activated during S phase to prevent later cell cycle events. However, the manner by which the regulatory signaling cascade induced by the cell wall integrity checkpoint feeds into the complex transcriptional network of cell cycle progression has not been fully investigated. Genome-wide transcriptional studies have revealed the transcription cascade of cell cycle-related transcription factors (6-9). Studies have shown major tr...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint

Negishi

Veis

Hollenstein

et al. 2016

Molecular and Cellular Biology

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“…One mechanism by which CN could enforce a cell cycle arrest is by downregulating expression of genes that drive the cell cycle forward. The S-phase TF Hcm1 is an established target of CN (Arsenault et al, 2015); however, an Hcm1 mutant that cannot interact with CN had no effect on CN-mediated response to stress (hcm1DP, Figures 1A and S1A). To determine if CN impacts the activities of other cell cycleregulatory TFs, RNA-seq was performed on samples from CaCl2 time course experiments and the average change in gene expression of targets of each TF was compared between control and FK506-treated cells.…”

Section: Cn Downregulates Multiple Clusters Of Cell Cycle Genesmentioning

confidence: 99%

“…A few cell cycle regulators have also been identified as CN targets, suggesting that CN may help coordinate the stress response with cell cycle arrest (Goldman et al, 2014;Mizunuma et al, 2001). Inactivation of the S-phase specific transcriptional activator Hcm1 by CN leads to decreased expression of its target genes, which include TFs that act at a later stage in the cell cycle (Arsenault et al, 2015). However, it is not known if CN impairs cell cycle-regulated gene expression solely through inactivation of Hcm1, or if CN regulates the TF network through additional mechanisms.…”

Section: Introductionmentioning

confidence: 99%

The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

et al. 2019

Preprint

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Upon exposure to environmental stressors, cells transiently arrest the cell cycle while they adapt and restore homeostasis. A challenge for all cells is to distinguish between diverse stress signals and coordinate the appropriate adaptive response with cell cycle arrest. Here we investigate the role of the stress-activated phosphatase calcineurin (CN) in this process and show that CN utilizes multiple pathways to control the cell cycle. Upon activation, CN inhibits transcription factors (TFs) that regulate the G1/S transition through activation of the stress-activated MAPK Hog1. In contrast, CN inactivates G2/M TFs through a combination of Hog1-dependent and -independent mechanisms. These findings demonstrate that CN and Hog1 act in a coordinated manner at multiple nodes of the cell cycle-regulatory network to rewire gene expression and arrest cells in response to stress. Our results suggest that crosstalk between CN and stress-activated MAPKs helps cells tailor their adaptive responses to specific stressors.

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A forkhead transcription factor contributes to the regulatory differences of pathogenicity in closely related fungal pathogens

Xie

et al. 2022

mLife

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Cryptococcus neoformans and its sister species Cryptococcus deuterogattii are important human fungal pathogens. Despite their phylogenetically close relationship, these two Cryptococcus pathogens are greatly different in their clinical characteristics. However, the determinants underlying the regulatory differences of their pathogenicity remain largely unknown. Here, we show that the forkhead transcription factor Hcm1 promotes infection in C. neoformans but not in C. deuterogattii. Monitoring in vitro and in vivo fitness outcomes of multiple clinical isolates from the two pathogens indicates that Hcm1 mediates pathogenicity in C. neoformans through its key involvement in oxidative stress defense. By comparison, Hcm1 is not critical for antioxidation in C. deuterogattii. Furthermore, we identified SRX1, which encodes the antioxidant sulfiredoxin, as a conserved target of Hcm1 in two Cryptococcus pathogens. Like HCM1, SRX1 had a greater role in antioxidation in C. neoformans than in C. deuterogattii. Significantly, overexpression of SRX1 can largely rescue the defective pathogenicity caused by the absence of Hcm1 in C. neoformans. Conversely, Srx1 is dispensable for virulence in C. deuterogattii. Overall, our findings demonstrate that the difference in the contribution of the antioxidant sulfiredoxin to oxidative stress defense underlies the Hcm1‐mediated regulatory differences of pathogenicity in two closely related pathogens.

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Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation

Cited by 17 publications

References 47 publications

The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint

The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint

The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

A forkhead transcription factor contributes to the regulatory differences of pathogenicity in closely related fungal pathogens

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