Characterization of a Candida albicans Mutant Defective in All MAPKs Highlights the Major Role of Hog1 in the MAPK Signaling Network

The success of Candida albicans as a pathogen relies on its ability to adapt and proliferate in different environmental niches. Pathways regulated by mitogen-activated protein kinases (MAPKs) are involved in sensing environmental conditions and developing an accurate adaptive response. Given the frequent cooperative roles of these routes in cellular functions, we have generated mutants defective in all combinations of the four described MAPKs in C. albicans and characterized its phenotype regarding sensitiveness to specific drugs, morphogenesis and interaction with host immune cells. We demonstrate that all MAPKs are dispensable in this yeast as a mutant defective in Cek1, Cek2, Mkc1 and Hog1 is viable although highly sensitive to oxidative and osmotic stress, displaying a specific pattern of sensitivity to antifungals. By comparing its phenotype with single, double and triple combinations of MAPK-deletion mutants we were able to unveil a Cek1-independent mechanism for Hog1 resistance to Congo red, and confirm the predominant effect of Hog1 on oxidative and osmotic adaptation. The quadruple mutant produces filaments under non-inducing conditions, but is unable to develop chlamydospores. Furthermore, cek1 cek2 mkc1 hog1 cells switch to the opaque state at high frequency, which is blocked by the ectopic expression of HOG1 suggesting a role of this kinase for phenotypic switching.

Download Full-text

The Vacuole and Mitochondria Patch (vCLAMP) Protein Mcp1 Is Involved in Maintenance of Mitochondrial Function and Mitophagy in Candida albicans

Frontiers in Microbiology ◽

10.3389/fmicb.2021.633380 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaolong Mao ◽

Li Yang ◽

Yiming Fan ◽

Jiazhen Wang ◽

Dongkai Cui ◽

...

Keyword(s):

Candida Albicans ◽

Carbon Sources ◽

Cellular Functions ◽

Core Component ◽

Membrane Contact Sites ◽

Contact Sites ◽

Mitochondrial Functions ◽

Abnormal Accumulation ◽

Membrane Contact

The vacuole and mitochondria patches (vCLAMPs) are novel membrane contact sites in yeast. However, their role in autophagy has not been elucidated so far. In this article, the role of Mcp1, one core component of vCLAMP, in mitophagy of Candida albicans was investigated. Deletion of MCP1 led to abnormal accumulation of enlarged mitochondria and attenuated stability of mitochondrial DNA (mtDNA) in C. albicans when cultured in non-fermentable carbon sources. Furthermore, the mcp1Δ/Δ mutant exhibited defective growth and degradation of Csp37-GFP. These results indicate that Mcp1 plays a crucial role in mitophagy and maintenance of mitochondrial functions under the non-fermentable condition. Interestingly, this deletion had no impact on degradation of Atg8 (the macroautophagy reporter) and Lap41 (the cytoplasm-to-vacuole targeting pathway marker) under SD-N medium. Moreover, deletion of MCP1 inhibited filamentous growth and impaired virulence of the pathogen. This study provides an insight to vCLAMPs in cellular functions and pathogenicity in C. albicans.

Download Full-text

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

International Journal of Molecular Sciences ◽

10.3390/ijms21031102 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1102 ◽

Cited By ~ 20

Author(s):

Shannon Lee ◽

Jens Rauch ◽

Walter Kolch

Keyword(s):

Drug Sensitivity ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Signal Transduction Pathways ◽

Erk Pathway ◽

Mapk Pathways ◽

Extracellular Signaling ◽

New Findings ◽

Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

Download Full-text

ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance

International Journal of Molecular Sciences ◽

10.3390/ijms20174153 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4153 ◽

Cited By ~ 2

Author(s):

Giovanna Capolongo ◽

Yoko Suzumoto ◽

Mariavittoria D’Acierno ◽

Mariadelina Simeoni ◽

Giovambattista Capasso ◽

...

Keyword(s):

Protein Kinases ◽

Mapk Signaling ◽

Signalling Pathway ◽

Renal Diseases ◽

Cellular Functions ◽

Acid Base ◽

Mapk Activity ◽

Extracellular Signal ◽

Wide Range ◽

Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

Download Full-text

p38 Mitogen-Activated Protein Kinase and Hematologic Malignancies

Archives of Pathology & Laboratory Medicine ◽

10.5858/133.11.1850 ◽

2009 ◽

Vol 133 (11) ◽

pp. 1850-1856

Author(s):

Yongdong Feng ◽

Jianguo Wen ◽

Chung-Che(Jeff) Chang

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Cell Types ◽

Hematologic Malignancies ◽

Mapk Signaling ◽

Chemotherapeutic Agents ◽

Mitogen Activated Protein Kinase ◽

Cellular Functions ◽

Downstream Effects ◽

Mitogen Activated Protein

Abstract Context.—p38 mitogen-activated protein kinase (MAPK) signaling has been implicated in responses ranging from apoptosis to cell cycle, induction of expression of cytokine genes, and differentiation. This plethora of activators conveys the complexity of the p38 pathway. This complexity is further complicated by the observation that the downstream effects of p38 MAPK activation may be different depending on types of stimuli, cell types, and various p38 MAPK isoforms involved. Objective.—This review focuses on the recent advancement of the p38 MAPK isoforms as well as the roles of p38 MAPK in hematologic malignancies. Data Sources.—Review of pertinent published literature and work in our laboratory. Conclusions.—In some hematologic malignancies, activation of p38 plays a key role in promoting or inhibiting proliferation and also in increasing resistance to chemotherapeutic agents. The importance of different p38 isoforms in various cellular functions has been acknowledged recently. Further understanding of these isoforms will allow the design of more specific inhibitors to target particular isoforms to maximize the treatment effect and minimize the side effects for treating hematopoietic malignancies.

Download Full-text

Role of Muramyl Dipeptide in Lipopolysaccharide-Mediated Biological Activity and Osteoclast Activity

Analytical Cellular Pathology ◽

10.1155/2018/8047610 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Hideki Kitaura ◽

Masahiko Ishida ◽

Keisuke Kimura ◽

Haruki Sugisawa ◽

Akiko Kishikawa ◽

...

Keyword(s):

Biological Activities ◽

Muramyl Dipeptide ◽

Mapk Signaling ◽

Osteoclast Formation ◽

Mitogen Activated Protein Kinase ◽

Immunological Activity ◽

Mitogen Activated Protein

Lipopolysaccharide (LPS) is an endotoxin and bacterial cell wall component that is capable of inducing inflammation and immunological activity. Muramyl dipeptide (MDP), the minimal essential structural unit responsible for the immunological activity of peptidoglycans, is another inflammation-inducing molecule that is ubiquitously expressed by bacteria. Several studies have shown that inflammation-related biological activities were synergistically induced by interactions between LPS and MDP. MDP synergistically enhances production of proinflammatory cytokines that are induced by LPS exposure. Injection of MDP induces lethal shock in mice challenged with LPS. LPS also induces osteoclast formation and pathological bone resorption; MDP enhances LPS induction of both processes. Furthermore, MDP enhances the LPS-induced receptor activator of NF-κB ligand (RANKL) expression and toll-like receptor 4 (TLR4) expression bothin vivoandin vitro. Additionally, MDP enhances LPS-induced mitogen-activated protein kinase (MAPK) signaling in stromal cells. Taken together, these findings suggest that MDP plays an important role in LPS-induced biological activities. This review discusses the role of MDP in LPS-mediated biological activities, primarily in relation to osteoclastogenesis.

Download Full-text

Bark tissue transcriptome analyses of inverted Populus yunnanensis cuttings reveal the crucial role of plant hormones in response to inversion

PeerJ ◽

10.7717/peerj.7740 ◽

2019 ◽

Vol 7 ◽

pp. e7740 ◽

Cited By ~ 1

Author(s):

An-Pei Zhou ◽

Pei-Hua Gan ◽

Dan Zong ◽

Xuan Fei ◽

Yuan-Yuan Zhong ◽

...

Keyword(s):

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Receptor Kinase ◽

Ethylene Response ◽

Mitogen Activated Protein ◽

Bark Tissue ◽

Plant Pathogen Interaction ◽

Transcriptomic Changes ◽

Stem Position

Inverted cuttings of Populus yunnanensis exhibit an interesting growth response to inversion. This response is characterized by enlargement of the stem above the shoot site, while the upright stem shows obvious outward growth below the shoot site. In this study, we examined transcriptome changes in bark tissue at four positions on upright and inverted cuttings of P. yunnanensis: position B, the upper portion of the stem; position C, the lower portion of the stem; position D, the bottom of new growth; and position E, the top of new growth. The results revealed major transcriptomic changes in the stem, especially at position B, but little alteration was observed in the bark tissue of the new shoot. The differentially expressed genes (DEGs) were mainly assigned to four pathways: plant hormone signal transduction, plant-pathogen interaction, mitogen-activated protein kinase (MAPK) signaling pathway-plant, and adenosine triphosphate-binding cassette (ABC) transporters. Most of these DEGs were involved in at least two pathways. The levels of many hormones, such as auxin (IAA), cytokinin (CTK), gibberellins (GAs), ethylene (ET), and brassinosteroids (BRs), underwent large changes in the inverted cuttings. A coexpression network showed that the top 20 hub unigenes at position B in the upright and inverted cutting groups were associated mainly with the BR and ET signaling pathways, respectively. Furthermore, brassinosteroid insensitive 1-associated receptor kinase 1 (BAK1) in the BR pathway and both ethylene response (ETR) and constitutive triple response 1 (CTR1) in the ET pathway were important hubs that interfaced with multiple pathways.

Download Full-text

Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Biomedicines ◽

10.3390/biomedicines9121759 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1759

Author(s):

Liliana Montella ◽

Margaret Ottaviano ◽

Vittorio Riccio ◽

Fernanda Picozzi ◽

Gaetano Facchini ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Langerhans Cell Histiocytosis ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Mapk Signaling ◽

Langerhans Cell ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

Download Full-text

Role of the Mitogen-Activated Protein Kinase Hog1p in Morphogenesis and Virulence of Candida albicans

Journal of Bacteriology ◽

10.1128/jb.181.10.3058-3068.1999 ◽

1999 ◽

Vol 181 (10) ◽

pp. 3058-3068 ◽

Cited By ~ 255

Author(s):

R. Alonso-Monge ◽

F. Navarro-García ◽

G. Molero ◽

R. Diez-Orejas ◽

M. Gustin ◽

...

Keyword(s):

Candida Albicans ◽

Map Kinase ◽

Pathogenic Fungi ◽

Mitogen Activated Protein Kinase ◽

Morphological Alterations ◽

Mitogen Activated Protein ◽

Drastic Increase ◽

Morphological Transitions ◽

Hyphal Formation

ABSTRACT The relevance of the mitogen-activated protein (MAP) kinase Hog1p in Candida albicans was addressed through the characterization of C. albicans strains without a functional HOG1 gene. Analysis of the phenotype ofhog1 mutants under osmostressing conditions revealed that this mutant displays a set of morphological alterations as the result of a failure to complete the final stages of cytokinesis, with parallel defects in the budding pattern. Even under permissive conditions,hog1 mutants displayed a different susceptibility to some compounds such as nikkomycin Z or Congo red, which interfere with cell wall functionality. In addition, the hog1 mutant displayed a colony morphology different from that of the wild-type strain on some media which promote morphological transitions in C. albicans. We show that C. albicans hog1 mutants are derepressed in the serum-induced hyphal formation and, consistently with this behavior, that HOG1 overexpression inSaccharomyces cerevisiae represses the pseudodimorphic transition. Most interestingly, deletion of HOG1 resulted in a drastic increase in the mean survival time of systemically infected mice, supporting a role for this MAP kinase pathway in virulence of pathogenic fungi. This finding has potential implications in antifungal therapy.

Download Full-text

Adenosine Triphosphate Activates Mitogen-Activated Protein Kinase in Human Granulosa-Luteal Cells*

Endocrinology ◽

10.1210/endo.142.4.8081 ◽

2001 ◽

Vol 142 (4) ◽

pp. 1554-1560 ◽

Cited By ~ 20

Author(s):

Chen-Jei Tai ◽

Sung Keun Kang ◽

Chii-Ruey Tzeng ◽

Peter C. K. Leung

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Intracellular Camp ◽

Human Ovary ◽

Luteal Cells ◽

Mitogen Activated Protein

Abstract ATP has been shown to activate the phospholipase C/diacylglycerol/protein kinase C (PKC) pathway. However, little is known about the downstream signaling events. The present study was designed to examine the effect of ATP on activation of the mitogen-activated protein kinase (MAPK) signaling pathway and its physiological role in human granulosa-luteal cells. Western blot analysis, using a monoclonal antibody that detected the phosphorylated forms of extracellular signal-regulated kinase-1 and -2 (p42mapk and p44 mapk, respectively), demonstrated that ATP activated MAPK in a dose- and time-dependent manner. Treatment of the cells with suramin (a P2 purinoceptor antagonist), neomycin (a phospholipase C inhibitor), staurosporin (a PKC inhibitor), or PD98059 (an MAPK/ERK kinase inhibitor) significantly attenuated the ATP-induced activation of MAPK. In contrast, ATP-induced MAPK activation was not significantly affected by pertussis toxin (a Gi inhibitor). To examine the role of Gs protein, the intracellular cAMP level was determined after treatment with ATP or hCG. No significant elevation of intracellular cAMP was noted after ATP treatment. To determine the role of MAPK in steroidogenesis, human granulosa-luteal cells were treated with ATP, hCG, or ATP plus hCG in the presence or absence of PD98059. RIA revealed that ATP alone did not significantly affect the basal progesterone concentration. However, hCG-induced progesterone production was reduced by ATP treatment. PD98059 reversed the inhibitory effect of ATP on hCG-induced progesterone production. To our knowledge, this is the first demonstration of ATP-induced activation of the MAPK signaling pathway in the human ovary. These results support the idea that the MAPK signaling pathway is involved in mediating ATP actions in the human ovary.

Download Full-text

CypA: a Potential Target of Tumor Radiotherapy and/or Chemotherapy

Current Medicinal Chemistry ◽

10.2174/0929867327666201029161055 ◽

2020 ◽

Vol 27 ◽

Author(s):

Man-Yu Chu ◽

He-Cheng Huang ◽

En-Ming Li ◽

Li-Yan Xu

Keyword(s):

Cancer Chemotherapy ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Cycle Arrest ◽

Mitogen Activated Protein ◽

Intracellular Target ◽

Related Proteins ◽

The Impact ◽

Mapk Signaling Pathways

: Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA also has been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, the impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.

Download Full-text