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

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.

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MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

Clinical Science ◽

10.1042/cs20070430 ◽

2008 ◽

Vol 115 (7) ◽

pp. 203-218 ◽

Cited By ~ 262

Author(s):

Anthony J. Muslin

Keyword(s):

Molecular Mechanisms ◽

Cardiovascular Health ◽

Mapk Pathway ◽

Science Research ◽

Pharmacological Therapy ◽

Model Systems ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

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Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

Cells ◽

10.3390/cells8101172 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1172 ◽

Cited By ~ 3

Author(s):

Chen ◽

Nelson ◽

Ávila ◽

Cubero

Keyword(s):

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Tract Cancer ◽

Response Differentiation ◽

Wide Range ◽

Pathophysiological Role ◽

Mitogen Activated Protein ◽

Extracellular Stimuli ◽

Signaling Components

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.

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New targets of urocortin-mediated cardioprotection

Journal of Molecular Endocrinology ◽

10.1677/jme-09-0148 ◽

2010 ◽

Vol 45 (2) ◽

pp. 69-85 ◽

Cited By ~ 28

Author(s):

Seán P Barry ◽

Kevin M Lawrence ◽

James McCormick ◽

Surinder M Soond ◽

Mike Hubank ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mitogen Activated Protein Kinase ◽

Related Factor ◽

Nuclear Factor ◽

Free Radical Damage ◽

Apoptosis Protein ◽

Wide Range ◽

Mitogen Activated Protein ◽

Crh Receptors

The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.

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

Eukaryotic Cell ◽

10.1128/ec.00465-07 ◽

2008 ◽

Vol 7 (5) ◽

pp. 826-835 ◽

Cited By ~ 52

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.

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Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1081-1095.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1081-1095 ◽

Cited By ~ 101

Author(s):

Nicole H. Purcell ◽

Dina Darwis ◽

Orlando F. Bueno ◽

Judith M. Müller ◽

Roland Schüle ◽

...

Keyword(s):

Mammalian Cells ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Erk Signaling ◽

Interacting Protein ◽

Hypertrophic Response ◽

Extracellular Signal ◽

Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

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Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies

Biochemical Journal ◽

10.1042/bj20080599 ◽

2008 ◽

Vol 413 (3) ◽

pp. 429-436 ◽

Cited By ~ 134

Author(s):

Yan Zeng ◽

Heidi Sankala ◽

Xiaoxiao Zhang ◽

Paul R. Graves

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Kinase Inhibitor ◽

Mapk Pathway ◽

Phosphorylation Site ◽

Mitogen Activated Protein Kinase ◽

Processing Bodies ◽

Mitogen Activated Protein

Ago (Argonaute) proteins are essential effectors of RNA-mediated gene silencing. To explore potential regulatory mechanisms for Ago proteins, we examined the phosphorylation of human Ago2. We identified serine-387 as the major Ago2 phosphorylation site in vivo. Phosphorylation of Ago2 at serine-387 was significantly induced by treatment with sodium arsenite or anisomycin, and arsenite-induced phosphorylation was inhibited by a p38 MAPK (mitogen-activated protein kinase) inhibitor, but not by inhibitors of JNK (c-Jun N-terminal kinase) or MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]. MAPKAPK2 (MAPK-activated protein kinase-2) phosphorylated bacterially expressed full-length human Ago2 at serine-387 in vitro, but not the S387A mutant. Finally, mutation of serine-387 to an alanine residue or treatment of cells with a p38 MAPK inhibitor reduced the localization of Ago2 to processing bodies. These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway.

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Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts

Biochemical Journal ◽

10.1042/bj20080279 ◽

2008 ◽

Vol 412 (3) ◽

pp. 435-445 ◽

Cited By ~ 18

Author(s):

Maja Jensen ◽

Jane Palsgaard ◽

Rehannah Borup ◽

Pierre de Meyts ◽

Lauge Schäffer

Keyword(s):

Gene Expression ◽

Insulin Receptor ◽

Mapk Pathway ◽

Receptor Activation ◽

Mitogen Activated Protein Kinase ◽

Single Chain ◽

Therapeutic Implications ◽

Insulin Mimetic ◽

Mitogen Activated Protein

Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications.

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Progranulin Regulates the Differentiation of Bone Marrow Mesenchymal Stem Cells Under Inflammation Through Focal Adhesion Kinase (FAK)/Mitogen-Activated Protein Kinase (MAPK) Pathway

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2248 ◽

2020 ◽

Vol 10 (2) ◽

pp. 281-286

Author(s):

Zirong Yang ◽

Hangbo Qu ◽

Hongting Jin

Keyword(s):

Osteogenic Differentiation ◽

Caspase 3 ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Control Group ◽

Alp Activity ◽

Mitogen Activated Protein ◽

Marrow Mesenchymal Stem Cells ◽

Group 5

Osteogenic differentiation of BMSCs is beneficial to the treatment of osteoarthritis. Progranulin (PGRN) is a chondrogenic factor. However, the role of progranulin in the differentiation of BMSCs under inflammation remains unclear. Rat BMSCs were isolated and divided into control group, inflammation group (treated with LPS), and PGRN group (5 and 10 /μM) followed by analysis of survival rate of BMSCs by MTT assay, Caspase 3 activity, ALP activity, expression of Runx2 and OP by real time PCR, level of MMP-3, TIMP-1, FAK and MAPK by Western blot and IL-6 and IL-10 secretion by ELISA. LPS treatment significantly inhibited BMSCs proliferation, increased Caspase 3 activity, decreased ALP activity, expression of Runx2 and OP, increased IL-6 secretion, decreased IL-10 secretion, increased MMP-3 expression, decreased expression of TIMP-1, FAK and p-P38 (P < 0.05). PGRN treatment on BMSCs under inflammation significantly promoted cell proliferation, decreased Caspase 3 activity, increased ALP activity, expression of Runx2 and OP, decreased IL-6 secretion, increased IL-10 secretion, decreased MMP-3 expression, and increased TIMP-1, FAK and p-P38 expression (P < 0.05) with more significant changes in the higher concentration. Under inflammation, BMSCs proliferation was inhibited, apoptosis was increased, and osteogenic differentiation was weakened. PGRN inhibits the proliferation of BMSCs and apoptosis, and promotes osteogenic differentiation by regulating FAK/MAPK pathway.

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

Molecular Biology of the Cell ◽

10.1091/mbc.e06-04-0315 ◽

2006 ◽

Vol 17 (10) ◽

pp. 4400-4410 ◽

Cited By ~ 130

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.

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