The Hog1 MAP Kinase Promotes the Recovery from Cell Cycle Arrest Induced by Hydrogen Peroxide in Candida albicans

ABSTRACT Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53val135 ) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19ARF was required for this effect, since p53 −/− ARF −/− double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19ARF on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53 −/− mdm2 −/− double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.

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Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.34.501 ◽

2011 ◽

Vol 34 (4) ◽

pp. 501-506 ◽

Cited By ~ 15

Author(s):

Kyohei Oyama ◽

Kiyoshi Takahashi ◽

Koichi Sakurai

Keyword(s):

Cell Cycle ◽

Hydrogen Peroxide ◽

Cell Cycle Arrest ◽

H9c2 Cells ◽

Cycle Arrest

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Oxidative stress induced by piperine leads to apoptosis in Candida albicans

Medical Mycology ◽

10.1093/mmy/myaa058 ◽

2020 ◽

Author(s):

Archana Thakre ◽

Vyankatesh Jadhav ◽

Rubina Kazi ◽

Amruta Shelar ◽

Rajendra Patil ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Cycle ◽

Candida Albicans ◽

Cell Cycle Arrest ◽

Resistant Strain ◽

Membrane Integrity ◽

Synergistic Activity ◽

Biofilm Growth ◽

Cycle Arrest ◽

Apoptosis Assay

Abstract Candida albicans is a member of pathogens with potential drug resistance threat that needs novel chemotherapeutic strategies. Considering the multifarious biological activities including bioenhancer activity, anti-Candida potential of piperine was evaluated against planktonic/biofilm and hyphal growth of C. albicans alone or in combination as a synergistic agent with fluconazole. Piperine inhibits planktonic growth at or less than 15 μg/ml, hyphae induction at 5 μg/ml concentration, and exhibits stage-dependent activity against biofilm growth of a fluconazole-resistant strain of C. albicans (ATCC10231). Though piperine couldn't kill inoculum completely at minimum inhibitory concentration (MIC), it is fungicidal at higher concentrations, as shown in apoptosis assay. FIC index values indicate that piperine exhibits excellent synergistic activity with fluconazole against planktonic (0.123) and biofilm (0.215) growth of an FLC resistant strain. Mode of anti-Candida activity was studied by identifying piperine responsive proteins wherein the abundance of 25 proteins involved in stress response, signal transduction and cell cycle were modulated (22 up and 3 down-regulated) significantly in response to piperine (MIC50). Modulation of the proteins involved suggests that piperine affects membrane integrity leading to oxidative stress followed by cell cycle arrest and apoptosis in C. albicans. Flow cytometry-based mitochondrial membrane potential (MMP), cell cycle and apoptosis assay, as well as real-time quantitative polymerase chain reaction analysis of selected genes, confirms piperine induced oxidative stress (TRR1), cell cycle arrest and apoptosis (CaMCA1). Based on our results, we conclude that piperine inhibits planktonic and difficult-to treat-biofilm growth of C. albicans by affecting membrane integrity thereby inducing oxidative stress and apoptosis. Lay Abstract Piperine inhibit Candida albicans growth (planktonic and biofilm) significantly in our study. Piperine exhibits excellent synergistic potential with fluconazole The proteome analysis suggests that piperine induced membrane damage leads to oxidative stress followed by cell cycle arrest and apoptosis.

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Role of Cdc42-Cla4 Interaction in the Pheromone Response of Saccharomyces cerevisiae

Eukaryotic Cell ◽

10.1128/ec.00102-06 ◽

2006 ◽

Vol 6 (2) ◽

pp. 317-327 ◽

Cited By ~ 17

Author(s):

Melanie Heinrich ◽

Tim Köhler ◽

Hans-Ulrich Mösch

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Map Kinase ◽

Cell Cycle Arrest ◽

Map Kinases ◽

Negative Regulator ◽

Cycle Arrest ◽

Mitogen Activated Protein ◽

Novel Alleles

ABSTRACT In Saccharomyces cerevisiae, the highly conserved Rho-type GTPase Cdc42 is essential for cell division and controls cellular development during mating and invasive growth. The role of Cdc42 in mating has been controversial, but a number of previous studies suggest that the GTPase controls the mitogen-activated protein (MAP) kinase cascade by activating the p21-activated protein kinase (PAK) Ste20. To further explore the role of Cdc42 in pheromone-stimulated signaling, we isolated novel alleles of CDC42 that confer resistance to pheromone. We find that in CDC42(V36A) and CDC42(V36A, I182T) mutant strains, the inability to undergo pheromone-induced cell cycle arrest correlates with reduced phosphorylation of the mating MAP kinases Fus3 and Kss1 and with a decrease in mating efficiency. Furthermore, Cdc42(V36A) and Cdc42(V36A, I182T) proteins show reduced interaction with the PAK Cla4 but not with Ste20. We also show that deletion of CLA4 in a CDC42(V36A, I182T) mutant strain suppresses pheromone resistance and that overexpression of CLA4 interferes with pheromone-induced cell cycle arrest and MAP kinase phosphorylation in CDC42 wild-type strains. Our data indicate that Cla4 has the potential to act as a negative regulator of the mating pathway and that this function of the PAK might be under control of Cdc42. In conclusion, our study suggests that control of pheromone signaling by Cdc42 not only depends on Ste20 but also involves interaction of the GTPase with Cla4.

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