La3+-Induced Extracellular Signal-Regulated Kinase (ERK) Signaling via a Metal-Sensing Mechanism Linking Proliferation and Apoptosis in NIH 3T3 Cells†

Biochemistry ◽  
2006 ◽  
Vol 45 (37) ◽  
pp. 11217-11225 ◽  
Author(s):  
Siwang Yu ◽  
Jian Hu ◽  
Xiaoda Yang ◽  
Kui Wang ◽  
Zhong Ming Qian
Keyword(s):  
Erk Signaling ◽  
3T3 Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Sensing Mechanism ◽  
Extracellular Signal ◽  
Proliferation And Apoptosis ◽  
Nih 3T3 ◽  
Metal Sensing ◽  
Nih 3T3 Cells

scholarly journals Induction of β3-Integrin Gene Expression by Sustained Activation of the Ras-Regulated Raf–MEK–Extracellular Signal-Regulated Kinase Signaling Pathway

2001 ◽  
Vol 21 (9) ◽  
pp. 3192-3205 ◽  
Author(s):  
Douglas Woods ◽  
Holly Cherwinski ◽  
Eleni Venetsanakos ◽  
Arun Bhat ◽  
Stephan Gysin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Signaling Pathway ◽  
Erk Signaling ◽  
Integrin Expression ◽  
3T3 Cells ◽  
Extracellular Signal ◽  
Integrin Gene ◽  
Β3 Integrin ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT Alterations in the expression of integrin receptors for extracellular matrix (ECM) proteins are strongly associated with the acquisition of invasive and/or metastatic properties by human cancer cells. Despite this, comparatively little is known of the biochemical mechanisms that regulate the expression of integrin genes in cells. Here we demonstrate that the Ras-activated Raf–MEK–extracellular signal-regulated kinase (ERK) signaling pathway can specifically control the expression of individual integrin subunits in a variety of human and mouse cell lines. Pharmacological inhibition of MEK1 in a number of human melanoma and pancreatic carcinoma cell lines led to reduced cell surface expression of α6- and β3-integrin. Consistent with this, conditional activation of the Raf-MEK-ERK pathway in NIH 3T3 cells led to a 5 to 20-fold induction of cell surface α6- and β3-integrin expression. Induced β3-integrin was expressed on the cell surface as a heterodimer with αv-integrin; however, the overall level of αv-integrin expression was not altered by Ras or Raf. Raf-induced β3-integrin was observed in primary and established mouse fibroblast lines and in mouse and human endothelial cells. Consistent with previous reports of the ability of the Raf-MEK-ERK signaling pathway to induce β3-integrin gene transcription in human K-562 erythroleukemia cells, Raf activation in NIH 3T3 cells led to elevated β3-integrin mRNA. However, unlike immediate-early Raf targets such as heparin binding epidermal growth factor and Mdm2, β3-integrin mRNA was induced by Raf in a manner that was cycloheximide sensitive. Surprisingly, activation of the Raf-MEK-ERK signaling pathway by growth factors and mitogens had little or no effect on β3-integrin expression, suggesting that the expression of this gene requires sustained activation of this signaling pathway. In addition, despite the robust induction of cell surface αvβ3-integrin expression by Raf in NIH 3T3 cells, such cells display decreased spreading and adhesion, with a loss of focal adhesions and actin stress fibers. These data suggest that oncogene-induced alterations in integrin gene expression may participate in the changes in cell adhesion and migration that accompany the process of oncogenic transformation.

scholarly journals Cyclic AMP Blocks Cell Growth through Raf-1-Dependent and Raf-1-Independent Mechanisms

2002 ◽  
Vol 22 (11) ◽  
pp. 3717-3728 ◽  
Author(s):  
Nicolas Dumaz ◽  
Yvonne Light ◽  
Richard Marais
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Cyclic Amp ◽  
3T3 Cells ◽  
Extracellular Signal ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT It is widely accepted that cyclic AMP (cAMP) can block cell growth by phosphorylating Raf-1 on serine 43 and inhibiting signaling to extracellular signal-regulated protein kinase. We show that the suppression of Raf-1 by cAMP is considerably more complex than previously reported. When cellular cAMP is elevated, Raf-1 is phosphorylated on three residues (S43, S233, and S259), which work independently to block Raf-1. Both Ras-dependent and Ras-independent processes are disrupted. However, when cAMP-insensitive versions of Raf-1 are expressed in NIH 3T3 cells, their growth is still strongly suppressed when cAMP is elevated. Thus, although Raf-1 appears to be an important cAMP target, other pathways are also targeted by cAMP, providing alternative mechanisms that lead to suppression of cell growth.

scholarly journals Downregulation of DUSP6, a negative regulator of oncogenic ERK signaling, by ACA‐28 induces apoptosis in NIH/3T3 cells overexpressing HER2/ErbB2

2020 ◽  
Author(s):  
Yuki Kanda ◽  
Ayami Mizuno ◽  
Teruaki Takasaki ◽  
Ryosuke Satoh ◽  
Kanako Hagihara ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Erk Signaling ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

scholarly journals Rrp15 affects cell cycle, proliferation, and apoptosis in NIH 3T3 cells

FEBS Open Bio ◽  
2016 ◽  
Vol 6 (11) ◽  
pp. 1085-1092 ◽  
Author(s):  
Tao Wu ◽  
Mei‐Xia Ren ◽  
Guo‐ping Chen ◽  
Zheng‐ming Jin ◽  
Gang Wang
Keyword(s):  
Cell Cycle ◽  
3T3 Cells ◽  
Proliferation And Apoptosis ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

scholarly journals ΔRaf-1:ER* Bypasses the Cyclic AMP Block of Extracellular Signal-Regulated Kinase 1 and 2 Activation but Not CDK2 Activation or Cell Cycle Reentry

2003 ◽  
Vol 23 (24) ◽  
pp. 9303-9317 ◽  
Author(s):  
Kathryn Balmanno ◽  
Tracy Millar ◽  
Martin McMahon ◽  
Simon J. Cook
Keyword(s):  
Cell Cycle ◽  
Cyclic Amp ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Cyclin A ◽  
3T3 Cells ◽  
Cell Cycle Reentry ◽  
Extracellular Signal ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT Elevation of cellular cyclic AMP (cAMP) levels inhibits cell cycle reentry in a variety of cell types. While cAMP can prevent the activation of Raf-1 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by growth factors, we now show that activation of ERK1/2 by ΔRaf-1:ER is insensitive to cAMP. Despite this, ΔRaf-1:ER-stimulated DNA synthesis is still inhibited by cAMP, indicating a cAMP-sensitive step downstream of ERK1/2. Although cyclin D1 expression has been proposed as an alternative target for cAMP, we found that cAMP could inhibit ΔRaf-1:ER-induced cyclin D1 expression only in Rat-1 cells, not in CCl39 or NIH 3T3 cells. ΔRaf-1:ER-stimulated activation of CDK2 was strongly inhibited by cAMP in all three cell lines, but cAMP had no effect on the induction of p21CIP1. cAMP blocked the fetal bovine serum (FBS)-induced degradation of p27KIP1; however, loss of p27KIP1 in response to ΔRaf-1:ER was less sensitive in CCl39 and Rat-1 cells and was completely independent of cAMP in NIH 3T3 cells. The most consistent effect of cAMP was to block both FBS- and ΔRaf-1:ER-induced expression of Cdc25A and cyclin A, two important activators of CDK2. When CDK2 activity was bypassed by activation of the ER-E2F1 fusion protein, cAMP no longer inhibited expression of Cdc25A or cyclin A but still inhibited DNA synthesis. These studies reveal multiple points of cAMP sensitivity during cell cycle reentry. Inhibition of Raf-1 and ERK1/2 activation may operate early in G1, but when this early block is bypassed by ΔRaf-1:ER, cells still fail to enter S phase due to inhibition of CDK2 or targets downstream of E2F1.

Hyperosmolality induces activation of cPKC and nPKC, a requirement for ERK1/2 activation in NIH/3T3 cells

2000 ◽  
Vol 278 (1) ◽  
pp. C102-C109 ◽  
Author(s):  
Shougang Zhuang ◽  
Syu-Ichi Hirai ◽  
Shigeo Ohno
Keyword(s):  
Selective Inhibition ◽  
3T3 Cells ◽  
Erk Activation ◽  
Kinase C ◽  
Extracellular Signal ◽  
Pkc Isoforms ◽  
Gf 109203X ◽  
Nih 3T3 ◽  
Pkc Activation ◽  
Nih 3T3 Cells

Protein kinase C (PKC) has been reported to be associated with the activation of extracellular signal-regulated kinase (ERK) by hyperosmolality. However, it is unclear whether hyperosmolality induces PKC activation and which PKC isoforms are involved in ERK activation. In this study, we demonstrate that NaCl increases total PKC activity and induces PKCα, PKCδ, and PKCε translocation from the cytosol to the membrane in NIH/3T3 cells, suggesting that hyperosmotic stress activates conventional PKC (cPKC) and novel PKC (nPKC). Further studies show that NaCl-inducible ERK1 and ERK2 (ERK1/2) activation is a consequence of cPKC and nPKC activation, because either downregulation with 12- O-tetradecanoylphorbol 13-acetate or selective inhibition of cPKC and nPKC by GF-109203X and rottlerin largely inhibited the stimulation of ERK1/2 phosphorylation by NaCl. In addition, we show that NaCl increases diacylglycerol (DAG) levels and that a phospholipase C (PLC) inhibitor, U-73122, inhibits NaCl-induced ERK1/2 phosphorylation. These results, together, suggest that a hyperosmotic NaCl-induced signaling pathway that leads to activation of ERK1/2 may sequentially involve PLC activation, DAG release, and cPKC and nPKC activation.

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