Business Startups: Cultural-Economic Controversy

The purpose of this paper is to examine whether national cultural differences and/or economic, macroeconomic indicators are dominant in explaining business startups in selected EU countries. Among Hofstede’s national cultural differences, we have used the individualismcollectiveness indexmeasuring preference behavior that promotes one’s self interest, while the power distance index measures tolerance of citizens in terms of social inequality in terms of superiors or subordinates; the uncertainty avoidance index reflects tolerance towards uncertainty and ambiguity among citizens, while the masculinity index measures whether the society is male centered (Hofstede 2003). The last variable in the model related to culture is the corruption index (Transparency International 2008), which reflects how sensitive the nation is towards corruption. Among the macroeconomic indicators we have looked at whether the firm birth rate in an economy is strongly influenced by the given average wage rate, overall productivity level among nations, index for profitability and real per capita GDP growth. Findings show that with some exclusion, cultural factors are as important as economic indicators in explaining national business startups. Towards this end we have used factor and principle component analysis towards explaining the strength of the relationship among the variables.business startups, Hoftstede’s model

Nicotine-induced phosphorylation of ERK in mouse primary cortical neurons: evidence for involvement of glutamatergic signaling and CaMKII.

Extracellular signal-regulated kinase (ERK) is activated in vivo in a number of brain areas by nicotine and other drugs of abuse. Here we show that nicotine stimulation of cultured mouse cortical neurons leads to a robust induction of ERK phosphorylation that is dependent on nicotine concentration and duration of exposure. Calcium/calmodulin-dependent protein kinase II activity is necessary for nicotine-induced ERK phosphorylation and neither cAMP-dependent protein kinase or protein kinase C appear to be involved. Activity of glutamate receptors, L-type voltage-gated calcium channels, and voltage-gated sodium channels are also required for nicotine-induced ERK phosphorylation. Nicotine-induced ERK phosphorylation was inhibited by high concentrations of mecamylamine, however it was not blocked by other broad nicotinic acetylcholine receptor (nAChR) inhibitors (including hexamethonium and chlorisondamine) or nAChR subtype selective inhibitors (such as methyllycaconitine, alpha-bungarotoxin, dihydro-beta-erythroidine, and α-conotoxin Au1B). In accord with these pharmacological results, nicotine-induced ERK phosphorylation was normal in primary cultures made from β2 or α7 nAChR subunit knockout mice. The α3/beta4 nAChR agonist cytisine did not induce ERK phosphorylation suggesting that α3/β4 nAChRs were not involved in this process. Taken together, these data define a necessary role for glutamatergic signaling and calcium/calmodulin-dependent protein kinase II in nicotine-induced ERK phosphorylation in cortical neurons and do not provide evidence for the involvement of classical nAChRs

Selective Desensitization of Growth Factor Signaling by Cell Adhesion to Fibronectin

Cell adhesion to the extracellular matrix is required to execute growth factor (GF)-mediated cell behaviors, such as proliferation. A major underlying mechanism is that cell adhesion enhances GF-mediated intracellular signals, such as extracellular signal-regulated kinase (Erk). However, because GFs use distinct mechanisms to activate Ras-Erk signaling, it is unclear whether adhesion-mediated enhancement of Erk signaling is universal to all GFs. We examined this issue by quantifying the dynamics of Erk signaling induced by epidermal growth factor, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) in NIH-3T3 fibroblasts. Adhesion to fibronectin-coated surfaces enhances Erk signaling elicited by epidermal growth factor but not by bFGF or PDGF. Unexpectedly, adhesion is not always a positive influence on GF-mediated signaling. At critical subsaturating doses of PDGF or bFGF, cell adhesion ablates Erk signaling; that is, adhesion desensitizes the cell to GF stimulation, rendering the signaling pathway unresponsive to GF. Interestingly, the timing of growth factor stimulation proved critical to the desensitization process. Erk activation significantly improved only when pre-exposure to adhesion was completely eliminated; thus, concurrent stimulation by GF and adhesion was able to partially rescue adhesion-mediated desensitization of PDGF- and bFGF-mediated Erk and Akt signaling. These findings suggest that adhesion-mediated desensitization occurs with rapid kinetics and targets a regulatory point upstream of Ras and proximal to GF receptor activation. Thus, adhesion-dependent Erk signaling is not universal to all GFs but, rather, is GF-specific with quantitative features that depend strongly on the dose and timing of GF exposure

Activation of Ras-ERK pathway by Fgf8 and its downregulation by Sprouty2 for the isthmus organizing activity

In the previous studies, we showed that strong Fgf8 signaling activates the Ras-ERK pathway to induce cerebellum. Here, we show importance of negative regulation of this pathway. 'Prolonged' activation of ERK by misexpression of _Fgf8b_ and dominant-negative _Sprouty2_ (_dnSprouty2_) did not change the fate of the mesencephalic alar plate. Downregulation of ERK activity using a MEK inhibitor, U0126, or by tetracycline dependent Tet-off system after co-expression of _Fgf8b_ and _dnSprouty2_, forced the mesencephalic alar plate to differentiate into cerebellum. We then paid attention to Mkp3. After misexpression of _dnMkp3_ and _Fgf8b_, slight downregulation of ERK activity occurred, which may be due to Sprouty2, and the mesencephalon transformed to the isthmus-like structure. The results indicate that ERK must be once upregulated and then be downregulated for cerebellar differentiation, and that differential ERK activity level established by negative regulators receiving Fgf8 signal may determine regional specificity of mesencephalon and metencephalon

ERK-1 MAP kinase prevents TNF-induced apoptosis through bad phosphorylation and inhibition of bax translocation in HeLa cells

Extracellular signal-regulated kinase (ERK) 1/2 signaling is involved in tumor cell survival through the regulation of Bcl-2 family members. To explore this further and to demonstrate the central role of the mitochondria in the ERK1/2 pathway we used the HeLa cellular model where apoptosis was induced by tumor necrosis factor (TNF) and cycloheximide (CHX). We show that HeLa cells overexpressing ERK-1 displayed resistance to TNF and CHX. HeLa cells overexpressing a kinase-deficient form of ERK-1 (K71R) were more sensitive to TNF and CHX. In the ERK-1 cells, Bad was phosphorylated during TNF + CHX treatment. In the HeLa wt cells and in the K71R clones TNF and CHX decreased Bad phosphorylation. ERK-1 cells treated with TNF and CHX did not release cytochrome c from the mitochondria. By contrast, HeLa wt and K71R clones released cytochrome c. Bax did not translocate to the mitochondria in ERK-1 cells treated with TNF + CHX. Conversely, HeLa wt and K71R clones accumulated Bax in the mitochondria. In the HeLa wt cells and in both ERK-1 transfectants Bid was cleaved and accumulated in the mitochondria. The caspase-8 inhibitor IETD-FMK and the mitochondrial membrane permeabilization inhibitor bongkrekic acid (BK), partially prevented cell death by TNF + CHX. Anisomycin, a c-Jun N-terminal kinases activator, increased TNF-killing. The ERK-1 cells were resistant to TNF and anisomycin, whereas K71R clones resulted more sensitive. Our study demonstrates that in HeLa cells the ERK-1 kinase prevents TNF + CHX apoptosis by regulating the intrinsic mitochondrial pathway through different mechanisms. Inhibition of the intrinsic pathway is sufficient to almost completely prevent cell death. © 2009 Wiley-Liss, Inc

Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK modul