Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is a hormone with multiple biological actions, produced predominantly by adipose tissue. In humans, plasma levels correlate with total body fat, and high concentrations occur in obese women. Among its functions, leptin is able to stimulate normal and tumor cell growth. We demonstrated that leptin induces aromatase activity in MCF-7 cells evidencing its important role in enhancing in situ estradiol production and promoting estrogen-dependent breast cancer progression. Estrogen receptor alpha (ERalpha), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. Taking into account that unliganded ERalpha is an effector of mitogen-activated protein kinase (MAPK) signal and that leptin is able, via Janus kinase, to activate the Ras-dependent MAPK pathway, in the present study we investigate the ability of leptin to transactivate ERalpha. We provided evidence that leptin is able to reproduce the classic features of ERalpha transactivation in a breast cancer cell line: nuclear localization, down-regulation of its mRNA and protein levels, and up-regulation of a classic estrogen-dependent gene such as pS2. Transactivation experiments with a transfected reporter gene for nuclear ER showed an activation of ERalpha either in MCF-7 or in HeLa cells. Using a dominant negative ERK2 or the MAPK inhibitor PD 98059, we showed that leptin activates the ERalpha through the MAPK pathway. The N-terminal transcriptional activation function 1 appears essential for the leptin response. Finally, it is worth noting that leptin exposure potentates also the estradiol-induced activation of ERalpha. Thus, we are able to demonstrate that the amplification of estrogen signal induced by leptin occurs through an enhancing in situ E(2) production as well as a direct functional activation of ERalpha.
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PMID:Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. 1498 28

In many cases, the process of cancer cell differentiation is associated with the programmed cell death. In the present study, interestingly, we found that eupatilin, one of the pharmacologically active ingredients of Artemisia asiatica that has been reported to induce apoptosis in human gastric cancer AGS cells, also triggers differentiation of these cells. Treatment of AGS cells with eupatilin induced cell cycle arrest at the G(1) phase with the concomitant induction of p21(cip1), a cell cycle inhibitor. This led us to test whether eupatilin may trigger AGS cells to differentiate into the matured phenotypes of epithelial cells and this phenomenon may be coupled to the apoptosis. Eupatilin induced changes of AGS cells to a more flattened morphology with increased cell size, granularity, and mitochondrial mass. It also markedly induced trefoil factor 1 (TFF1), a gene responsible for the gastrointestinal cell differentiation. Eupatilin dramatically induced redistribution of tight junction proteins such as occludin and ZO-1, and F-actin at the junctional region between cells. It also induced phosphorylation of extracellular signal-regulated kinase 2 and p38 kinase. Blockade of ERK signaling by PD098059 or the dominant-negative ERK2 significantly reduced eupatilin-induced TFF1 and p21 expression as well as ZO-1 redistribution, indicating that ERK cascades may mediate eupatilin-induced AGS cell differentiation. Collectively, our results suggest that eupatilin acts as a novel anti-tumor agent by inducing differentiation of gastrointestinal cancer cells rather than its direct role in inducing apoptotic cell death.
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PMID:Eupatilin exhibits a novel anti-tumor activity through the induction of cell cycle arrest and differentiation of gastric carcinoma AGS cells. 1928 88

The aim of this study was to determine whether the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway is involved in genistein- and equol-induced cell proliferation and estrogen receptor (ER) alpha transactivation. For MCF-7 human breast cells, low concentrations of genistein and equol enhanced proliferation and induced MCF-7 cells to enter the S-phase. Genistein- and equol-induced cell proliferation and S-phase entry were blocked by the ERalpha antagonists 4-hydroxytamoxifen and ICI 182,780 and by the mitogen-activated protein kinase 1/2 inhibitor U0126. These data indicated that ERalpha and mitogen-activated protein extracellular kinase/ERK signaling were required for the effects of genistein/equol on cell growth and cell cycle progression. Genistein and equol induced delayed and prolonged activation of ERK1/2. Inhibition of ERK1/2 phosphorylation by U0126 led to complete suppression of genistein- and equol-induced estrogen response element reporter activity and to suppression of the estrogen-responsive gene pS2. The anti-estrogen ICI had no effect on genistein- and equol-induced ERK1/2 phosphorylation. These results suggest that activation of ERK1/2 lies upstream of ER-mediated transcription, and that ERK1/2 activation is necessary for the transactivation of ERalpha. In conclusion, genistein and equol elicit a delayed activation of ERK1/2, and this activation appears to be involved in the proliferation of breast cancer cells and estrogen-dependent transcriptional activation.
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PMID:Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-alpha-mediated transcription in MCF-7 breast cancer cells. 1942 79