Calcium Activates Serum Response Factor-Dependent Transcription By A Ras- and Elk-1-Independent Mechanism That Involves a Ca<sup>2+</sup>/Calmodulin-Dependent Kinase

Miranti, Cindy K.; Ginty, David D.; Huang, Gloria S.; Chatila, Talal A.; Greenberg, Michael E.

doi:10.1128/mcb.15.7.3672

Cited by 211 publications

(190 citation statements)

References 60 publications

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“…In many studies, the K-ras gene has been proven to take part in cell growth regulation by activating MAP kinase to activate transcription factor ELK-1 (Marais et al, 1993;Miranti et al, 1995). In 1996, Xing et al found that introduction of activated ras oncogene into PC12 cells regulated gene expression by activating RAF and MAP kinase and then RSK2 of pp90RSK family to phosphorylate CREB (Xing et al, 1996;Cesare et al, 1998;Beaupre et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Chen

et al. 2002

Br J Cancer

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The result of our previous study has shown that the K-ras mutant (pK568MRSV) transfected human adrenocortical cells can significantly increase cortisol production and independently cause cell transformation. The aim of this study is to investigate the effect of the active K-ras oncogene on the cortisol production in normal human adrenocortical cells. First we used isopropyl thiogalactoside to induce the inducible mutant K-ras expression plasmid, pK568MRSV, in the stable transfected human adrenocortical cells. The result showed that the increase of RasGTP levels in transfected cells was time-dependent after isopropyl thiogalactoside induction. Additionally, results from Western blot analysis revealed significant elevation in phosphorylation of c-Raf-1 and Mitogen-activated protein kinase. We also detected the levels of mRNA encoding Cholesterol side-chain cleavage enzyme (P450 SCC ), 17a-Hydroxylase/17,20-lyase (P450 c17 ) and 3b-Hydroxysteroid dehydrogenase (3bHSD) were increased in human adrenocortical cells transfected with mutant K-ras after IPTG treatment. The increase of mRNA amount in P450 scc P450 c17 and 3bHSD and the elevation of cortisol level were inhibited with a pretreatment of PD098059, a specific extracellular signal-regulated kinase inhibitor. In our previous report, we proved that lovastatin, a pharmacological inhibitor of p21 ras function, also reversed the increase of cortisol level in mutant K-ras stably transfected human adrenocortical cells. Taken together, these findings proved that the active mutant Ras enhanced not only cell proliferation but also steroidogenesis in steroidogenic phenotype cells by activating Raf-MEK-MAPK related signal transduction pathway. Therefore, we believe that K-ras mutants influence regulation of steroidogenesis in adrenocortical cells through RAF-MEK-MAPK pathway.

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Section: Discussionmentioning

confidence: 99%

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Chen

et al. 2002

Br J Cancer

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“…The direct mechanism of Rho induction of the SRE is unclear, however it was recently found that Rho and LIM kinase control of actin treadmilling and the control of free actin concentrations in the cells was critical for Rho and LIM kinase activation of the SRE (Sotiropoulos et al, 1999). In an additional pathway, increased calcium concentrations can also activate the SRE independently of the TCF site through a CaMK dependent pathway (Miranti et al, 1995). Since CaMK can also activate CREB, it is possible that the FAP1 site may also mediate calcium induction of the c-fos enhancer along with the SRE.…”

Section: Discussionmentioning

confidence: 99%

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

2000

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The c-fos enhancer can be activated by many signaling pathways through distinct elements of the enhancer. The enhancer contains at its core the serum response element (SRE) that binds serum response factor (SRF). On the 5' side of the SRE is a site for p62 TCF which binds only when SRF is bound as well. p62 TCF is encoded by three ets-related genes, Elk-1, SAP1 and SAP2. Each of these factors contain a transcriptional activation domain that is activated by phosphorylation by MAP kinases. On the 3' side of the SRE is the`c-fos AP1 site' (FAP1) whose role has been less clear. We ®nd here that the FAP1 site contributes strongly to phorbol ester (TPA) and Erk MAP kinase activation of the c-fos enhancer and that both the p62 TCF and FAP1 sites are required for e ective activation of the enhancer. We further ®nd that the FAP1 site binds ATF1 and CREB from HeLa nuclear extracts and that the phosphorylation of these factors is induced by TPA. ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62 TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.

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“…In T lymphocytes, the activation of nuclear factor of activated T cells (NF-AT) is quantitatively correlated with the intracellular concentration of Ca 2+ (Negulescu et al, 1994). The in¯ux of Ca 2+ through voltage-sensitive Ca 2+ channels also stimulates serum response factor (SRF)-dependent transcription in the pheochromocytoma cell line PC12 (Miranti et al, 1995). Sequencing of the 5'¯anking region of the mouse MKP-1 gene revealed the presence of several consensus sequences that include one CRE, two SP1 sites, two CTF/NF1-like sites, and one E-box motif (Noguchi et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

et al. 1997

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Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is a dual-speci®city protein phosphatase encoded by an immediate-early gene responsive to growth factors and stress. The MKP-1 protein selectively inactivates MAP kinases in vitro by dephosphorylation of the regulatory Thr and Tyr residues. Little is known on the mechanisms that regulate MKP-1 gene expression. Here, we demonstrate that Ca 2+ is both necessary and su cient for the induction of MKP-1 gene expression. Treatment of Rat1 ®broblasts with the Ca 2+ chelating agent BAPTA completely suppressed serum-induced MKP-1 expression in a dose-and timedependent manner. The inhibitory e ect of BAPTA was observed at the level of the protein and the mRNA. Importantly, Ca 2+ chelation blocked the induction of MKP-1 expression in response to all stimuli tested and in di erent cell types. Increasing the intracellular concentration of Ca 2+ with the ionophore A23187 was su cient to induce MKP-1 mRNA and protein expression in rat ®broblasts. We also provide evidence that activation of MAP kinases is not an absolute requirement for induction of the MKP-1 gene. Exposure of rat ®broblasts to A23187 induced MKP-1 expression without activating the JNK and p38 MAP kinase pathways. Also, inhibition of the ERK pathway with the selective MEK inhibitor PD98059 did not interfere with serumstimulated MKP-1 mRNA expression. These results will help de®ne the regulatory mechanisms that govern MKP-1 gene transcription in target cells.

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Calcium Activates Serum Response Factor-Dependent Transcription By A Ras- and Elk-1-Independent Mechanism That Involves a Ca²⁺/Calmodulin-Dependent Kinase

Cited by 211 publications

References 60 publications

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

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Calcium Activates Serum Response Factor-Dependent Transcription By A Ras- and Elk-1-Independent Mechanism That Involves a Ca2+/Calmodulin-Dependent Kinase

Cited by 211 publications

References 60 publications

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

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Calcium Activates Serum Response Factor-Dependent Transcription By A Ras- and Elk-1-Independent Mechanism That Involves a Ca²⁺/Calmodulin-Dependent Kinase