Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways, which are not present in normal prostate epithelial cells. During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic anti-prostate cancer effect. As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5alpha-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) 'bulky' steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.
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PMID:Combinatorial androgen receptor targeted therapy for prostate cancer. 1695 23

This study investigated the effects of progesterone (P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice. The administration of P4 (4 mg/kg) for 3 consecutive days beginning on the 0-2nd day after the first BrdU-injection (BrdU-D(0-2)) produced an approximately twofold increase in the number of 28- and 56-day-old BrdU(+) cells in comparison to the controls, whereas it did not alter the number of 24/48-h-old BrdU(+) cells. P4 preferentially promoted the survival of newborn neurons when administered at BrdU-D(5-7), but not at BrdU-D(10-12) and BrdU-D(15-17). Androstenedione (Ad), testosterone (TE), or estradiol (E2) at the same-dose of P4, when administered at BrdU-D(0-2), could not replicate the effect of P4, while the inhibition of 5alpha-reductase by finasteride did not affect the P4-action, indicating that the P4-effect is exerted by P4 itself but not by its metabolites. On the other hand, the P4R antagonist RU486 partially suppressed the P4-effect, while inhibitors for Src, MEK, or PI3K totally suppressed the P4-effect. Finally, the P4-enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory, which was P4R-dependent. These findings suggest that P4 enhances the survival of newborn neurons through P4R and/or the Src-ERK and PI3K pathways independent of its influence on cell proliferation, which is well correlated with the potentiated spatial cognitive function of P4-treated animals.
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PMID:Progesterone promotes the survival of newborn neurons in the dentate gyrus of adult male mice. 1947 50