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 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 HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fengjie Jiang ◽  
Xiaozhu Tang ◽  
Chao Tang ◽  
Zhen Hua ◽  
Mengying Ke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Aberrant Expression ◽  
The Stability ◽  
Induced Apoptosis ◽  
Proliferation In Vitro

AbstractN6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern.

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

ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways

1998 ◽  
Vol 275 (4) ◽  
pp. H1209-H1215 ◽  
Author(s):  
Peter A. Wilden ◽  
Yehenew M. Agazie ◽  
Rebecca Kaufman ◽  
Stephen P. Halenda
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathways ◽  
Cellular Proliferation ◽  
Muscle Cells ◽  
Mitogen Activated Protein Kinase ◽  
Pi3k Signaling ◽  
Dependent Manner ◽  
Mitogen Activated Protein

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.

scholarly journals Transcriptional Repressor ERF Is a Ras/Mitogen-Activated Protein Kinase Target That Regulates Cellular Proliferation

1999 ◽  
Vol 19 (6) ◽  
pp. 4121-4133 ◽  
Author(s):  
Lionel le Gallic ◽  
Dionyssios Sgouras ◽  
Gregory Beal ◽  
George Mavrothalassitis
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Cellular Proliferation ◽  
Transcriptional Repressor ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Mitogen Activated Protein ◽  
Ets Family

ABSTRACT A limited number of transcription factors have been suggested to be regulated directly by Erks within the Ras/mitogen-activated protein kinase signaling pathway. In this paper we demonstrate that ERF, a ubiquitously expressed transcriptional repressor that belongs to the Ets family, is physically associated with and phosphorylated in vitro and in vivo by Erks. This phosphorylation determines the ERF subcellular localization. Upon mitogenic stimulation, ERF is immediately phosphorylated and exported to the cytoplasm. The export is blocked by specific Erk inhibitors and is abolished when residues undergoing phosphorylation are mutated to alanine. Upon growth factor deprivation, ERF is rapidly dephosphorylated and transported back into the nucleus. Phosphorylation-defective ERF mutations suppress Ras-induced tumorigenicity and arrest the cells at the G0/G1 phase of the cell cycle. Our findings strongly suggest that ERF may be important in the control of cellular proliferation during the G0/G1 transition and that it may be one of the effectors in the mammalian Ras signaling pathway.

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.

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