scholarly journals Regulation of the Intracellular Localization of Foxo3a by Stress-Activated Protein Kinase Signaling Pathways in Skeletal Muscle Cells

2009 ◽  
Vol 30 (2) ◽  
pp. 470-480 ◽  
Author(s):  
Stephan Clavel ◽  
Sandrine Siffroi-Fernandez ◽  
Anne Sophie Coldefy ◽  
Kim Boulukos ◽  
Didier F. Pisani ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Muscle Atrophy ◽  
Nuclear Import ◽  
Nuclear Export ◽  
Nuclear Translocation ◽  
Muscle Cells ◽  
C2c12 Cells ◽  
C2c12 Myotubes

ABSTRACT Muscle atrophy is a debilitating process associated with many chronic wasting diseases, like cancer, diabetes, sepsis, and renal failure. Rapid loss of muscle mass occurs mainly through the activation of protein breakdown by the ubiquitin proteasome pathway. Foxo3a transcription factor is critical for muscle atrophy, since it activates the expression of ubiquitin ligase Atrogin-1. In several models of atrophy, inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway induces nuclear import of Foxo3a through an Akt-dependent process. This study aimed to identify signaling pathways involved in the control of Foxo3a nuclear translocation in muscle cells. We observed that after nuclear import of Foxo3a by PI3K/Akt pathway inhibition, activation of stress-activated protein kinase (SAPK) pathways induced nuclear export of Foxo3a through CRM1. This mechanism involved the c-Jun NH2-terminal kinase (JNK) signaling pathway and was independent of Akt. Likewise, we showed that inhibition of p38 induced a massive nuclear relocalization of Foxo3a. Our results thus suggest that SAPKs are involved in the control of Foxo3a nucleocytoplasmic translocation in C2C12 cells. Moreover, activation of SAPKs decreases the expression of Atrogin-1, and stable C2C12 myotubes, in which the p38 pathway is constitutively activated, present partial protection against atrophy.

scholarly journals Identification of Withania somnifera-Silybum marianum-Trigonella foenum-graecum Formulation as a Nutritional Supplement to Contrast Muscle Atrophy and Sarcopenia

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 49
Author(s):  
Laura Salvadori ◽  
Manuela Mandrone ◽  
Tommaso Manenti ◽  
Catia Ercolani ◽  
Luca Cornioli ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Withania Somnifera ◽  
Myoblast Differentiation ◽  
C2c12 Myotubes ◽  
Silybum Marianum ◽  
Trigonella Foenum Graecum ◽  
Age Related

Background: Muscle atrophy, i.e., the loss of skeletal muscle mass and function, is an unresolved problem associated with aging (sarcopenia) and several pathological conditions. The imbalance between myofibrillary protein breakdown (especially the adult isoforms of myosin heavy chain, MyHC) and synthesis, and the reduction of muscle regenerative potential are main causes of muscle atrophy. Methods: Starting from one-hundred dried hydroalcoholic extracts of medical plants, we identified those able to contrast the reduction of C2C12 myotube diameter in well-characterized in vitro models mimicking muscle atrophy associated to inflammatory states, glucocorticoid treatment or nutrient deprivation. Based on their ability to rescue type II MyHC (MyHC-II) expression in atrophying conditions, six extracts with different phytochemical profiles were selected, mixed in groups of three, and tested on atrophic myotubes. The molecular mechanism underpinning the effects of the most efficacious formulation, and its efficacy on myotubes obtained from muscle biopsies of young and sarcopenic subjects were also investigated. Results: We identified WST (Withania somnifera, Silybum marianum, Trigonella foenum-graecum) formulation as extremely efficacious in protecting C2C12 myotubes against MyHC-II degradation by stimulating Akt (protein kinase B)-dependent protein synthesis and p38 MAPK (p38 mitogen-activated protein kinase)/myogenin-dependent myoblast differentiation. WST sustains trophism in C2C12 and young myotubes, and rescues the size, developmental MyHC expression and myoblast fusion in sarcopenic myotubes. Conclusion: WST strongly counteracts muscle atrophy associated to different conditions in vitro. The future validation in vivo of our results might lead to the use of WST as a food supplement to sustain muscle mass in diffuse atrophying conditions, and to reverse the age-related functional decline of human muscles, thus improving people quality of life and reducing social and health-care costs.

14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPKα/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice

2021 ◽  
pp. 1-19
Author(s):  
Chih-Chieh Chen ◽  
Chong-Kuei Lii ◽  
Chia-Wen Lo ◽  
Yi-Hsueh Lin ◽  
Ya-Chen Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Time Dependent ◽  
Antidiabetic Activity ◽  
C2c12 Myotubes ◽  
Dependent Manner ◽  
Compound C

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells

2007 ◽  
Vol 292 (6) ◽  
pp. E1555-E1567 ◽  
Author(s):  
Brian J. Krawiec ◽  
Gerald J. Nystrom ◽  
Robert A. Frost ◽  
Leonard S. Jefferson ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Mrna Expression ◽  
Muscle Atrophy ◽  
Ubiquitin Ligases ◽  
C2c12 Cells ◽  
Skeletal Muscle Atrophy ◽  
Compound C ◽  
Mrna Content ◽  
Amp Activated Protein Kinase

The hypothesis of the present study was that exposure of differentiated muscle cells to agonists of the AMP-activated protein kinase (AMPK) would increase the mRNA content of the muscle-specific ubiquitin ligases muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). C2C12 cells were incubated with incremental doses of 5-aminoimidazol-4-carboximide ribonucleoside (AICAR) or metformin for 24 h. Both MAFbx and MuRF1 mRNA increased dose dependently in response to these AMPK activators. AICAR, metformin, and 2-deoxy-d-glucose produced time-dependent alterations in ubiquitin ligase expression, typified by a biphasic pattern of expression marked by an acute repression followed by a sustained induction. AMPK-activating treatments in conjunction with dexamethasone produced a pronounced synergistic effect on ligase mRNA expression at later time points. This cooperative response occurred in the absence of a dexamethasone-dependent increase in AMPK expression or activity, as determined by immunoblotting for phosphorylation and expression of AMPKα and its downstream target acetyl-CoA carboxylase (ACC). These responses elicited by AMPK activation singly or in combination with dexamethasone did not extend to the mRNA expression of the UBR box family E3s UBR1/E3αI and UBR2/E3αII. Treatment with the AMPK inhibitor compound C prevented increases in MAFbx and MuRF1 mRNA in response to serum deprivation, as well as AICAR and dexamethasone treatment individually or jointly. Stimulation of AMPK activity in vivo via AICAR injection increased both MAFbx and MuRF1 mRNA in murine skeletal muscle. These data suggest that activation of AMPK in skeletal muscle results in a specific upregulation of MAFbx and MuRF1, responses that are reminiscent of the proposed atrophic transcriptional program executed under various conditions of skeletal muscle wasting. Therefore, AMPK may be a critical component of the intercalated network of signaling pathways governing skeletal muscle atrophy, where its input acts to modify anti- and proatrophic signals to influence gene expression in reaction to catabolic perturbations.

Characterization of PACAP receptors and signaling pathways in rabbit gastric muscle cells

1997 ◽  
Vol 272 (6) ◽  
pp. G1391-G1399 ◽  
Author(s):  
K. S. Murthy ◽  
J. G. Jin ◽  
J. R. Grider ◽  
G. M. Makhlouf
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Muscle Cells ◽  
Cyclic Monophosphate ◽  
Pituitary Adenylate Cyclase ◽  
Gastric Muscle ◽  
Pacap Receptors ◽  
G Protein Coupled ◽  
Camp Formation ◽  
Cgmp Formation

Pituitary adenylate cyclase-activating peptide (PACAP) receptors and their signaling pathways were characterized in dispersed rabbit gastric muscle cells. 125I-PACAP-27 and 125I-vasoactive intestinal peptide (VIP) binding to muscle cells were inhibited equally by PACAP and VIP (mean inhibitory concentration 0.8 to 1.3 nM) and desensitized to the same extent (70-80%) by exposure to either peptide. PACAP, like VIP, increased cytosolic free Ca2+ and the formation of L-[3H]citrulline, NO-3/NO-2, guanosine 3',5'-cyclic monophosphate (cGMP), and adenosine 3'5'-cyclic monophosphate (cAMP) and induced relaxation (mean effective concentration 1.8 +/- 0.1 nM) that was partly inhibited by NG-nitro-L-arginine (L-NNA), VIP-(10-28), and PACAP 6-38. L-[3H]citrulline and cGMP formation were blocked by nifedipine, L-NNA, and pertussis toxin (PTx), implying activation of a G protein-coupled, Ca(2+)-calmodulin-dependent nitric oxide (NO) synthase. PACAP-induced relaxation was inhibited to the same extent (46-49%) by nifedipine, L-NNA, PTx, and the protein kinase G inhibitor KT-5823; the inhibition reflected the component of relaxation mediated by the NO-cGMP pathway. The residual relaxation was abolished by the protein kinase A inhibitor H-89. The pattern of inhibition of all responses was identical to that observed with VIP. Desensitization with VIP or PACAP abolished cAMP formation but had no effect on L-[3H]citrulline and cGMP formation induced by either peptide. Receptor protection with VIP or PACAP preserved fully all responses (L-[3H]citrulline, cGMP, and cAMP formation and relaxation) to either peptide. The complete cross-competition, cross-desensitization, cross-antagonism, and cross-protection of receptors by either VIP or PACAP are consistent with interaction of both peptides with the same receptors; the receptors consist of two classes, each coupled to a distinct signaling pathway.

scholarly journals Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 284 ◽  
Author(s):  
Min-Kyeong Lee ◽  
Jeong-Wook Choi ◽  
Youn Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Protective Effects ◽  
Factor I ◽  
Igf I ◽  
Foxo Signaling Pathway

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy.

scholarly journals Regulation of PRAK Subcellular Location by p38 MAP Kinases

2003 ◽  
Vol 14 (6) ◽  
pp. 2603-2616 ◽  
Author(s):  
Liguo New ◽  
Yong Jiang ◽  
Jiahuai Han
Keyword(s):  
Protein Kinase ◽  
Nuclear Import ◽  
Nuclear Export ◽  
Map Kinases ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Localization Sequence ◽  
Resting Cells ◽  
Cellular Activation ◽  
Mitogen Activated Protein

The p38 mitogen-activated protein kinase (MAPK) pathway plays an important role in cellular responses to inflammatory stimuli and environmental stress. p38 regulated/activated protein kinase (PRAK, also known as mitogen-activated protein kinase activated protein kinase 5 [MAPKAPK5]) functions downstream of p38α and p38β in mediating the signaling of the p38 pathway. Immunostaining revealed that endogenous PRAK was predominantly localized in the cytoplasm. Interestingly, ectopically expressed PRAK was localized in the nucleus and can be redistributed by coexpression of p38α or p38β to the locations of p38α and p38β. Mutations in the docking groove on p38α/p38β, or the p38-docking site in PRAK, disrupted the PRAK-p38 interaction and impaired the ability of p38α and p38β to redistribute ectopically expressed PRAK, indicating that the location of PRAK could be controlled by its docking interaction with p38α and p38β. Although the majority of PRAK molecules were detected in the cytoplasm, PRAK is consistently shuttling between the cytoplasm and the nucleus. A sequence analysis of PRAK shows that PRAK contains both a putative nuclear export sequence (NES) and a nuclear localization sequence (NLS). The shuttling of PRAK requires NES and NLS motifs in PRAK and can be regulated through cellular activation induced by stress stimuli. The nuclear content of PRAK was reduced after stimulation, which resulted from a decrease in the nuclear import of PRAK and an increase in the nuclear export of PRAK. The nuclear import of PRAK is independent from p38 activation, but the nuclear export requires p38-mediated phosphorylation of PRAK. Thus, the subcellular distribution of PRAK is determined by multiple factors including its own NES and NLS, docking interactions between PRAK and docking proteins, phosphorylation of PRAK, and cellular activation status. The p38 MAPKs not only regulate PRAK activity and PRAK activation-related translocation, but also dock PRAK to selected subcellular locations in resting cells.

scholarly journals RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Mei Han ◽  
Lianghui You ◽  
Yanting Wu ◽  
Nan Gu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Rna Sequencing ◽  
Metabolic Diseases ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
C2c12 Myotubes ◽  
Insulin Resistant

Abstract Insulin resistance (IR) has been considered as the common pathological basis and developmental driving force for most metabolic diseases. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators in modulation of glucose and lipid metabolism. However, the comprehensive profile of lncRNAs in skeletal muscle cells under the insulin resistant status and the possible biological effects of them were not fully studied. In this research, using C2C12 myotubes as cell models in vitro, deep RNA-sequencing was performed to profile lncRNAs and mRNAs between palmitic acid-induced IR C2C12 myotubes and control ones. The results revealed that a total of 144 lncRNAs including 70 up-regulated and 74 down-regulated (|fold change| > 2, q < 0.05) were significantly differentially expressed in palmitic acid-induced insulin resistant cells. In addition, functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases revealed that the target genes of the differentially expressed lncRNAs were significantly enriched in fatty acid oxidation, lipid oxidation, PPAR signaling pathway, and insulin signaling pathway. Moreover, Via qPCR, most of selected lncRNAs in myotubes and db/db mice skeletal muscle showed the consistent expression trends with RNA-sequencing. Co-expression analysis also explicated the key lncRNA–mRNA interactions and pointed out a potential regulatory network of candidate lncRNA ENSMUST00000160839. In conclusion, the present study extended the skeletal muscle lncRNA database and provided novel potential regulators for future genetic and molecular studies on insulin resistance, which is helpful for prevention and treatment of the related metabolic diseases.

Differential Gene Signature and Signaling Pathways in Childhood Burkitt (BL) vs Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4142-4142
Author(s):  
Nancy S. Day ◽  
Janet Ayello ◽  
Ian Waxman ◽  
Evan Shereck ◽  
Catherine McGuinn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Cytokine Receptor ◽  
Receptor Interaction ◽  
Signal Pathways ◽  
Type I

Abstract The prognosis and treatment of both major forms of advanced childhood B-NHL (BL and DLBCL) is similar with short and intensive multi-agent chemotherapy (Cairo/Patte et al., Blood, 2007 and Patte/Cairo et al., Blood, 2007). Despite both BL and DLBCL being germinal center derived, our recent cytogenetic results of BL vs DLBCL in the FAB LMB 96 study have demonstrated significant differences in secondary chromosomal aberrations in BL vs DLBCL and a differential prognosis based on secondary cytogenetic findings (Poirel/Cairo/Patte, Blood, 2003a). Thus, we sought to identify genes that could uniquely differentiate childhood BL vs DLBCL and discover potential genetic mechanisms of differential molecular pathogenesis and to determine the signal pathways that contribute to the genetic disparity between these two histological types of childhood B-NHL. Nine BL (7 patient samples and 2 cell lines, Raji and Ramos) and 3 DLBCL (1 patient sample and 2 cell lines, Pfeiffer and DB) were compared. Total RNA was isolated, reverse transcribed to cDNA biotinylated cRNA and hybridized to Affymetrix U133A_2 as we have previously described (Jiang/Cairo et al., Journal of Immunology, 2004). Data were analyzed using Agilent GeneSpring 7.3. Signal intensities were compared using one way ANOVA and Welch Test for statistical analysis. Two-fold changes between BL and DLBCL were considered as significant (p<0.05). KEGG Pathways were evaluated for the genes identified. There were 120 genes over-expressed and 217 genes under-expressed in BL vs DLBCL. BL expressed significantly higher level of Ki-67 (a measure of lymphoma-cell proliferation) than DLBCL (2.68F). BL also expressed higher level of the pro-apoptotic gene, p53 compared to DLBCL (1.46F). Over-expressed genes in BL vs DLBCL included TNFSF10 (11.87F), RHOQ (3.16F), PIP5K1B (5.22F) among many others. The genes significantly under-expressed in BL vs DLBCL included PIGL (0.45F), Inositol (myo)-1 (or 4)-monophosphatase 1 (IMPA1; 0.28F), cAMP-dependent regulatory type I, alpha protein kinase (PRKAR1A; 0.37F) among many others. TNFSF10 induces apoptosis in transformed and tumor cells and is known to participate in pathways including cytokine-cytokine receptor interaction and induction of apoptosis through DR3 and DR4/5 death receptors. PIP5K1B is involved in the Rho signaling pathway and PIGL catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis. Since activation of IL3R-mediated cAMP-dependent protein kinase leads to increased cell survival, we searched gene expression profiles in BL vs DLBCL that were involved in IL signaling pathways. The genes that were identified to be over-expressed in BL vs DLBCL included IL2RG (2.24F), IL8RB, IL18 receptor accessory protein (IL18RAP), IL18, IL18R1, and IL1R2 (natural log values of 11.11, 22.95, 2.16, 1.73 and 11.84, respectively in BL vs non-detectable values in DLBCL). Taken together, since IL1, IL2, IL8, and IL18 all belong to IL1 super family, these results suggest significant involvement of TNF (TRAIL) and IL1 super family via cytokine-cytokine receptor interaction and activation of the Rho signaling pathway in Burkitt vs DLBCL lymphomagenesis.

scholarly journals Changes in the Balance of Phosphoinositide 3-Kinase/Protein Kinase B (Akt) and the Mitogen-activated Protein Kinases (ERK/p38MAPK) Determine a Phenotype of Visceral and Vascular Smooth Muscle Cells

1999 ◽  
Vol 145 (4) ◽  
pp. 727-740 ◽  
Author(s):  
Ken'ichiro Hayashi ◽  
Masanori Takahashi ◽  
Kazuhiro Kimura ◽  
Wataru Nishida ◽  
Hiroshi Saga ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Signaling Pathways ◽  
Protein Kinase B ◽  
Muscle Cells ◽  
Akt Pathway ◽  
Vascular Smcs ◽  
Igf I ◽  
Phosphoinositide 3 Kinase

The molecular mechanisms behind phenotypic modulation of smooth muscle cells (SMCs) remain unclear. In our recent paper, we reported the establishment of novel culture system of gizzard SMCs (Hayashi, K., H. Saga, Y. Chimori, K. Kimura, Y. Yamanaka, and K. Sobue. 1998. J. Biol. Chem. 273: 28860–28867), in which insulin-like growth factor-I (IGF-I) was the most potent for maintaining the differentiated SMC phenotype, and IGF-I triggered the phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB(Akt)) pathway. Here, we investigated the signaling pathways involved in de-differentiation of gizzard SMCs induced by PDGF-BB, bFGF, and EGF. In contrast to the IGF-I–triggered pathway, PDGF-BB, bFGF, and EGF coordinately activated ERK and p38MAPK pathways. Further, the forced expression of active forms of MEK1 and MKK6, which are the upstream kinases of ERK and p38MAPK, respectively, induced de-differentiation even when SMCs were stimulated with IGF-I. Among three growth factors, PDGF-BB only triggered the PI3-K/PKB(Akt) pathway in addition to the ERK and p38MAPK pathways. When the ERK and p38MAPK pathways were simultaneously blocked by their specific inhibitors or an active form of either PI3-K or PKB(Akt) was transfected, PDGF-BB in turn initiated to maintain the differentiated SMC phenotype. We applied these findings to vascular SMCs, and demonstrated the possibility that the same signaling pathways might be involved in regulating the vascular SMC phenotype. These results suggest that changes in the balance between the PI3-K/PKB(Akt) pathway and the ERK and p38MAPK pathways would determine phenotypes of visceral and vascular SMCs. We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which induced de-differentiation of surrounding normal SMCs.

Sign in / Sign up

Export Citation Format

Share Document