EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fosand p27Kip1

Mahimainathan, Lenin; Ghosh‐Choudhury, Nandini; Venkatesan, Balachandar; Danda, R S; Choudhury, Goutam Ghosh

doi:10.1152/ajprenal.00277.2004

Cited by 32 publications

(35 citation statements)

References 51 publications

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“…The activation of ERKs occurred via MEK1 in a PI3K-dependent manner. Consistent with our studies, the inhibition of PI3K pathway blocks platelet-derived growth factor-and epidermal growth factor-stimulated c-FOS expression via ERK signaling (45,46). The PI3K inhibitor blocked CS-induced ERK1/2 activation (Fig.…”

Section: Discussionsupporting

confidence: 89%

A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

Zhang

Adiseshaiah

Kalvakolanu

et al. 2006

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 89%

A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

Zhang

Adiseshaiah

Kalvakolanu

et al. 2006

Journal of Biological Chemistry

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“…This scenario involves EGF activation of phosphatidylinositol 3'-kinase (PI 3-kinase) and the subsequent phosphorylation of Atk/PKB serine/ threonine kinase. The PI 3-kinase pathway is activated following EGF stimulation [24,30,33]. PI 3-kinase in turn phosphorylates phosphatidylinositides on the 3' position to produce phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 and 3,4-triphosphate (PtdIns3,4)P 3 [46].…”

Section: Discussionmentioning

confidence: 99%

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

Joyner

Aboulafia

Damron

et al. 2008

Clin Orthop Relat Res

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Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFb, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFb and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFb1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.

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“…A Dual-Luciferase assay kit was purchased from Promega. The plasmids expressing the dominant-negative (DN) p85 subunit of PI3K (pSR␣⌬p85), DN Akt (Akt(K179M)), DN Erk2, Gal4-Elk-1, and Gal4-luciferase and adenoviral (Ad) vectors expressing PTEN (Ad PTEN) and hemagglutinin-tagged DN Akt were described previously (13)(14)(15)(16). The DN RasN17 expression plasmid was a kind gift from Dr. Julian Downward (Imperial Cancer Research Foundation, London, UK).…”

Section: Methodsmentioning

confidence: 99%

“…The data were plotted as mean luciferase activity/g of protein as arbitrary units Ϯ S.E. as described (13,19).…”

Section: Methodsmentioning

confidence: 99%

Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

Ghosh‐Choudhury

Mandal

Choudhury

2007

Journal of Biological Chemistry

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132

109

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Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.Statins block cholesterol biosynthesis by competitively inhibiting the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase, which converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate (1). Statins have recently been shown to reduce osteoclast activity and to stimulate osteoblast differentiation in vitro and bone formation in vivo (2-4). The role of statins in increasing bone mineral density in experimental animals and their role in protecting against fractures in cross-sectional or retrospective case control studies have led to testing this group of drugs for osteoporosis management (3, 5-9).The lipophilic statins, viz. lovastatin, fluvastatin, simvastatin, and mevastatin, specifically activate the bone morphogenetic protein-2 (BMP-2) 3 gene promoter (3). The more water-soluble pravastatin does not, however, induce BMP-2 promoter activity or BMP-2 mRNA and protein levels (10). Pravastatin does not stimulate new bone formation in neonatal murine calvaria (3). Transient exposure of bone cultures to lipophilic statins is sufficient to initiate the cascade resulting in bone formation, most probably because of the local production of BMP-2. Simvastatin-induced differentiation of MC3T3-E1 cells is accompanied by an increase in mRNA expression of BMP-2, vascular endothelial growth factor, alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (11). Although the expression of Cbfa-1/Runx2 was found to be unchanged by simvastatin treatment in the previous study (11), an earlier report demonstrated that lovastatin increases Cbfa-1/Runx2 expression while stimulating osteogenic differentiation of bone marrow mesenchymal cells (12). These studies clearly demonstrate a role for statins in osteoblast differentiation.Here we report that lovastatin stimulates osteoblast differentiation by activating phosphatidylinositol...

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EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fosand p27^Kip1

Cited by 32 publications

References 51 publications

A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

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