scholarly journals Transcription Factors Pcr1 and Atf1 Have Distinct Roles in Stress- and Sty1-Dependent Gene Regulation

2008 ◽  
Vol 7 (5) ◽  
pp. 826-835 ◽  
Author(s):  
Miriam Sansó ◽  
Madelaine Gogol ◽  
José Ayté ◽  
Chris Seidel ◽  
Elena Hidalgo
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Transcriptional Responses ◽  
Repressive Effect ◽  
Mitogen Activated Protein ◽  
Promote Cell Survival ◽  
Stress Dependent ◽  
Microarray Analyses ◽  
Stress Activation

ABSTRACT The mitogen-activated protein kinase Sty1 is essential for the regulation of transcriptional responses that promote cell survival in response to different types of environmental stimuli in Schizosaccharomyces pombe. Upon stress activation, Sty1 reversibly accumulates in the nucleus, where it stimulates gene expression via the Atf1 transcription factor. The Atf1 protein forms a heterodimer with Pcr1, but the specific role of this association is controversial. We have carried out a comparative analysis of strains lacking these proteins individually. We demonstrate that Atf1 and Pcr1 have similar but not identical roles in S. pombe, since cells lacking Pcr1 do not share all the phenotypes reported for Δatf1 cells. Northern blot and microarray analyses demonstrate that the responses to specific stresses of cells lacking either Pcr1 or Atf1 do not fully overlap, and even though most Atf1-dependent genes induced by osmotic stress are also Pcr1 dependent, a subset of genes require only the presence of Atf1 for their induction. Whereas binding of Atf1 to most stress-dependent genes requires the presence of Pcr1, we demonstrate here that Atf1 can bind to the Pcr1-independent promoters in a Δpcr1 strain in vivo. Furthermore, these analyses show that both proteins have a global repressive effect on stress-dependent and stress-independent genes.

scholarly journals Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Hayato Nakagawa ◽  
Shin Maeda
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Effects ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

scholarly journals The MAPK Hog1p Modulates Fps1p-dependent Arsenite Uptake and Tolerance in Yeast

2006 ◽  
Vol 17 (10) ◽  
pp. 4400-4410 ◽  
Author(s):  
Michael Thorsen ◽  
Yujun Di ◽  
Carolina Tängemo ◽  
Montserrat Morillas ◽  
Doryaneh Ahmadpour ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transcriptional Response ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Mechanisms ◽  
Signaling Mechanisms ◽  
Mitogen Activated Protein ◽  
Detoxification Systems ◽  
Arsenic Sensing

Arsenic is widely distributed in nature and all organisms possess regulatory mechanisms to evade toxicity and acquire tolerance. Yet, little is known about arsenic sensing and signaling mechanisms or about their impact on tolerance and detoxification systems. Here, we describe a novel role of the S. cerevisiae mitogen-activated protein kinase Hog1p in protecting cells during exposure to arsenite and the related metalloid antimonite. Cells impaired in Hog1p function are metalloid hypersensitive, whereas cells with elevated Hog1p activity display improved tolerance. Hog1p is phosphorylated in response to arsenite and this phosphorylation requires Ssk1p and Pbs2p. Arsenite-activated Hog1p remains primarily cytoplasmic and does not mediate a major transcriptional response. Instead, hog1Δ sensitivity is accompanied by elevated cellular arsenic levels and we demonstrate that increased arsenite influx is dependent on the aquaglyceroporin Fps1p. Fps1p is phosphorylated on threonine 231 in vivo and this phosphorylation critically affects Fps1p activity. Moreover, Hog1p is shown to affect Fps1p phosphorylation. Our data are the first to demonstrate Hog1p activation by metalloids and provides a mechanism by which this kinase contributes to tolerance acquisition. Understanding how arsenite/antimonite uptake and toxicity is modulated may prove of value for their use in medical therapy.

scholarly journals In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

2002 ◽  
Vol 169 (10) ◽  
pp. 5955-5961 ◽  
Author(s):  
Barun K. Choudhury ◽  
James S. Wild ◽  
Rafeul Alam ◽  
Dennis M. Klinman ◽  
Istvan Boldogh ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Cpg Oligodeoxynucleotide ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

scholarly journals Involvement of I-BAR protein IRSp53 in tumor cell growth via extracellular microvesicle secretion

2020 ◽  
Author(s):  
Hooi Ting Hu ◽  
Naoto Sasakura ◽  
Daisuke Matsubara ◽  
Naoko Furusawa ◽  
Masahiro Mukai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Culture Medium ◽  
Cellular Proliferation ◽  
Squamous Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Mice Model ◽  
Bar Domain ◽  
Mitogen Activated Protein

AbstractCellular protrusions mediated by the membrane-deforming I-BAR domain protein IRSp53 are involved in cell migration, including metastasis. However, the role of IRSp53 in cell proliferation remains unclear. Here, we examined the role of IRSp53 in cell proliferation and found that it acts through secretion. Coculture of gingiva squamous carcinoma Ca9-22 cells and their IRSp53-knockout cells restored proliferation to parental Ca9-22 cell levels, suggesting possible secretion dependent on IRSp53. Notably, the amounts of microvesicle fraction proteins that were secreted into the culture medium were reduced in the IRSp53-knockout cells. The IRSp53-knockout cells exhibited decreased phosphorylation of mitogen-activated protein kinase, suggesting the decrease in the proliferation signals. The phosphorylation was restored by the addition of the microvesicles. In mice xenograft Ca9-22 cells, IRSp53-containing particles were secreted around the xenograft, indicating that IRSp53-dependent secretion occurs in vivo. In a tumor mice model, IRSp53 deficiency elongated lifespan. In some human cancers, the higher levels of IRSp53 mRNA expression was found to be correlated with shorter survival years. Therefore, IRSp53 is involved in tumor progression and secretion for cellular proliferation.

scholarly journals Hyperglycemia Acutely Increases Monocyte Extracellular Signal-Regulated Kinase Activity in Vivo in Humans

2001 ◽  
Vol 86 (3) ◽  
pp. 1301-1305 ◽  
Author(s):  
Giulio Ceolotto ◽  
Alessandra Gallo ◽  
Michelangelo Sartori ◽  
Roberto Valente ◽  
Elisabetta Baritono ◽  
...  
Keyword(s):  
Normal Subjects ◽  
Mitogen Activated Protein Kinase ◽  
Glucose Levels ◽  
Extracellular Signal ◽  
Patients With Diabetes ◽  
Mitogen Activated Protein ◽  
Negative Role ◽  
Long Term Prognosis

Glycemic spikes may negatively affect the long-term prognosis of patients with diabetes. Extracellular signal-regulated kinases (ERKs) are intracellular mediators of cell proliferation, and they can be activated in response to high glucose levels. However, the modifications of their activity in response to hyperglycemia have been poorly investigated, in vivo, in humans. Thus, we sought to determine in circulating monocytes: 1) the role of hyperglycemia in ERKs activity and phosphorylation, and 2) whether hyperglycemia affects mitogen-activated protein kinase kinase (MEK) activity and mitogen-activated protein phosphatase-1 (MKP-1) expression. These goals were performed in five normal subjects. Baseline monocyte ERKs activity was 60 ± 5 pmol/min·mg protein; when exogenous hyperglycemia was induced, both monocyte ERKs activity (81 ± 11 pmol/min·mg protein; P < 0.05) and phosphorylation significantly increased (P < 0.01). MEK activity was significantly increased by hyperglycemia (1251 ± 136 vs. 2000 ± 42 cpm; P = 0.0017), whereas no changes were observed in MKP-1 expression. We conclude that hyperglycemia acutely stimulates ERKs activity and phosphorylation in human monocytes by the MEK pathway in vivo. These findings may be relevant in understanding the negative role of acute hyperglycemia on monocyte pathophysiology.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
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.

scholarly journals Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
N. Ronkina ◽  
K. Schuster-Gossler ◽  
F. Hansmann ◽  
H. Kunze-Schumacher ◽  
I. Sandrock ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Knockout Mice ◽  
Germ Line ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase 6/extracellular signal-regulated kinase 3 (MAPK6/ERK3) is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary dysfunction and by defects in function, activation, and positive selection of T cells. To study the role of ERK3 in vivo, we generated mice carrying a conditional Erk3 allele with exon 3 flanked by loxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)-cre and a clear reduction of the protein kinase MK5 is detected, providing the first evidence for the existence of the ERK3/MK5 signaling complex in vivo. In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile and do not display pulmonary hypoplasia, acute respiratory failure, abnormal T-cell development, reduction of thymocyte numbers, or altered T-cell selection. Hence, ERK3 is dispensable for pulmonary and T-cell functions. The perinatal lethality and lung and T-cell defects of the previous ERK3 knockout mice are likely due to ERK3-unrelated effects of the inserted lacZ-neomycin resistance cassette. The knockout mouse of the closely related atypical MAPK ERK4/MAPK4 is also normal, suggesting redundant functions of both protein kinases.

scholarly journals Chemotherapy-induced miR-141/MAP4K4 signaling suppresses progression of colorectal cancer

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Feifei Wang ◽  
Lianmei Zhao ◽  
Juan Zhang ◽  
Zesong Meng ◽  
Chaoxi Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mitogen Activated Protein Kinase ◽  
Chemotherapy Drugs ◽  
Reverse Transcription Quantitative Pcr ◽  
Mitogen Activated Protein ◽  
Resistance To Chemotherapy ◽  
Protein Kinase Kinase

One of the treatment failures for colorectal cancer (CRC) is resistance to chemotherapy drugs. miRNAs have been demonstrated to be a new regulator of pathobiological processes in various tumors. While few studies have explored the specific role of miR-141 in mediating 5-fluorouracil (5-FU) sensitivity of CRC cells, the present study aimed to detect the contribution of miR-141 in 5-FU sensitivity. The CRC cells viability was measured by MTS assay and cell colony forming. The expression of miR-141 and its downstream targets were assessed by reverse transcription quantitative PCR, Western blotting, and immunohistochemistry. The functional assays were conducted using CRC cells and nude mice. At the present study, we found overexpression of miR-141 could inhibit proliferation, migration, tumor-forming and invasive potential of CRC cells in vitro and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was verified as a directed target of miR-141. The combination treatment of miR-141 with 5-FU, directly targetting MAP4K4, could better inhibit invasion and metastasis of CRC cells colony than either one alone. Furthermore, overexpression of miR-141, targetting MAP4K4, enhanced the effected of 5-FU and suppressed the malignant biological behaviors, in vivo. Our findings showed that 5-FU inhibited malignant behavior of human CRC cells in vitro and in vivo by enhancing the efficiency of miR-141. Our data suggested that targetting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC.

scholarly journals The Ebola virus soluble glycoprotein contributes to viral pathogenesis by activating the MAP kinase signaling pathway

2021 ◽  
Vol 17 (9) ◽  
pp. e1009937
Author(s):  
Wakako Furuyama ◽  
Kyle Shifflett ◽  
Heinz Feldmann ◽  
Andrea Marzi
Keyword(s):  
Signaling Pathway ◽  
Ebola Virus ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Huh7 Cells ◽  
Mitogen Activated Protein

Ebola virus (EBOV) expresses three different glycoproteins (GPs) from its GP gene. The primary product, soluble GP (sGP), is secreted in abundance during infection. EBOV sGP has been discussed as a potential pathogenicity factor, however, little is known regarding its functional role. Here, we analyzed the role of sGP in vitro and in vivo. We show that EBOV sGP has two different functions that contribute to infectivity in tissue culture. EBOV sGP increases the uptake of virus particles into late endosomes in HEK293 cells, and it activates the mitogen-activated protein kinase (MAPK) signaling pathway leading to increased viral replication in Huh7 cells. Furthermore, we analyzed the role of EBOV sGP on pathogenicity using a well-established mouse model. We found an sGP-dependent significant titer increase of EBOV in the liver of infected animals. These results provide new mechanistic insights into EBOV pathogenicity and highlight EBOV sGP as a possible therapeutic target.

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