Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.1.17 (ornithine decarboxylase)
 6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cross-talk in vivo between two signalling pathways activated by testosterone via intracellular androgen receptor, and induced by damage to renal tubules evoked by anti-folate [N(10)-propargyl-5,8-dideazafolic acid (CB 3717)] or folate is reported. We show that CB 3717/folate induces the expression of the hepatocyte growth factor (HGF)/c-Met signalling system in injured kidneys in which a significant, but transient, elevation of the HGF mRNA level occurs. It is followed by a severalfold increase in the c-Met transmembrane receptor message that persists for up to 24 h. The c-Met expression is also positively controlled by testosterone, which induces a significant increase in its mRNA level that is abolished by an anti-androgen, casodex. However, when testosterone and anti-folate/folate are administered sequentially, a substantial (3.5-4.0-fold) decrease in the increase of c-Met expression caused by CB 3717/folate alone occurs. Similarly, testosterone-induced ornithine decarboxylase (ODC) mRNA level and activity are decreased 2.8-7.7-fold when the androgen is applied together with CB 3717. Antagonism between these pathways is also visible under physiological conditions in the kidneys of male mice in which, owing to elevated endogenous testosterone levels, neither the ODC activity nor the mRNA level is induced by anti-folate/folate, whereas the c-Met message response to these drugs is significantly decreased. Our results document a substantial negative regulation of c-Met and ODC gene expression as a result of the cross-talk between testosterone-activated and HGF-activated pathways and suggest a sex-differentiated response to injury of mouse kidneys.
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PMID:Cross-talk between steroid-receptor-mediated and cell-membrane-receptor-mediated signalling pathways results in the in vivo modulation of c-Met and ornithine decarboxylase gene expression in mouse kidney. 1113 96

Time-dependent changes in polyamine metabolism and c-Myc expression are reported in kidney of mice treated with cisplatin, a widely used anticancer drug. We show that cisplatin significantly induces the expression of two enzymes critical to proper homeostasis of cellular polyamines, ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT). We also document the cross-talk between signalling pathway(s) induced by cisplatin injury to renal tubules and the testosterone/androgen receptor pathway. Their interaction results in a decrease in testosterone-induced ODC activity and ODC mRNA level, and in differential modulation of SSAT expression. Moreover, cisplatin and antifolate CB 3717, another nephrotoxic drug examined, severalfold up-regulate expression of c-Myc mRNA, albeit with different kinetics. However, cisplatin, contrary to CB 3717, does not induce renal hepatocyte growth factor (HGF)/c-Met expression being without effect on HGF mRNA level and significantly down-regulating c-Met transmembrane receptor message. In conclusion, these in vivo studies document significant cisplatin-induced modulation of polyamine biosynthesis/degradation and up-regulation of c-Myc expression, and suggest that c-Myc transcription factor is involved in the induction of ODC in kidney injured with antifolate, but not with cisplatin.
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PMID:Cisplatin up-regulates the in vivo biosynthesis and degradation of renal polyamines and c-Myc expression. 1527 53

Polyamines play an important role in cell growth and differentiation, while their overproduction has potentially oncogenic consequences. Polyamine homoeostasis, a critical determinant of cell fate, is precisely tuned at the level of biosynthesis, degradation and transport. The enzymes ODC (ornithine decarboxylase), AdoMetDC (S-adenosylmethionine decarboxylase) and SSAT (spermidine/spermine N(1)-acetyltransferase) are critical for polyamine pool maintenance. Our experiments were designed to examine the expression of these enzymes in testosterone-induced hypertrophic and antifolate-induced hyperplastic mouse kidney, characterized by activation of AR (androgen receptor) and HGF (hepatocyte growth factor) membrane receptor c-Met respectively. The expression of these key enzymes was up-regulated by antifolate CB 3717 injury-evoked activation of HGF/c-Met signalling. In contrast, activation of the testosterone/AR pathway remarkably induced a selective increase in ODC expression without affecting other enzymes. Studies in catecholamine-depleted kidneys point to a synergistic interaction between the signalling pathways activated via cell membrane catecholamine receptors and AR, as well as c-Met. We found that this cross-talk modulated the expression of ODC and AdoMetDC, enzymes limiting polyamine biosynthesis, but not SSAT. This is in contrast with the antagonistic cross-talk between AR- and c-Met-mediated signalling which negatively regulated the expression of ODC, but affected neither AdoMetDC nor SSAT.
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PMID:Nuclear and membrane receptor-mediated signalling pathways modulate polyamine biosynthesis and interconversion. 1737 Dec 83

Cross-talk between two signal transduction pathways leads to a negative regulation of androgen-induced ornithine decarboxylase (ODC) gene expression in the mouse kidney. One pathway is triggered by testosterone via the intracellular androgen receptor, AR, and the other is induced by antifolate CB 3717 or folate via hepatocyte growth factor and its cell membrane receptor c-Met. Here we report the studies of the expression of AR and c-Myc transcription factors involved in ODC transactivation. Administration of CB 3717 or folate decreased the expression of AR. In contrast, testosterone did not modify AR mRNA content but augmented the AR protein. Furthermore, we demonstrate that administration of folate, but not testosterone, increases c-Myc transcript and protein level. We also document that activation of both examined pathways does not decrease the testosterone-induced AR protein level, but markedly increases c-Myc protein which is nearly 2-fold up-regulated compared to its level evoked solely by testosterone. We suspect that this pronounced increase of c-Myc protein might have functional consequences mirrored by down-regulated expression of AR target genes, among them ODC.
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PMID:Androgen receptor and c-Myc transcription factors as putative partners in the in vivo cross-talk between androgen receptor-mediated and c-Met-mediated signalling pathways. 1752 86

We have shown that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis, reduces the invasive and metastatic properties of MDA-MB-435 breast cancer cells while activating multiple signal transduction pathways, including MAPK, Stat3, Stat1, and JNK. Since the activity of these signaling mechanisms is frequently regulated by upstream tyrosine kinases (TKs), we tested whether non-receptor and receptor TKs may be involved in the signaling and biological effects of DFMO in MDA-MB-435 cells. Treatment with DFMO (1 mM for 48 h) did not affect Src phosphorylation (Tyr 416). Administration of the Src-family members inhibitor PP-1 (1 microM), blocked Src phosphorylation in the absence and in the presence of DFMO, but did not block the signaling effects of DFMO (increased phosphorylation of Stat3, Stat1, ERK and JNK). PP-1 treatment, on the other hand, inhibited the invasiveness of MDA-MB-435 cells in matrigel and potentiated the anti-invasive effect of DFMO. Next, we focused on the role of receptor TK. Western analysis of cell lysates from MDA-MB-435 cells failed to show the presence of EGF-R and HER-2neu but demonstrated the expression of c-Met, the receptor for hepatocyte growth factor (HGF). Therefore, we tested the effect of DFMO on the HGF/c-Met pathway which is strongly implicated in the progression of human breast cancer. We found that DFMO treatment blocked HGF-induced c-Met phosphorylation in MDA-MB-435 cells, suggesting that its anti-invasion action may be mediated, at least in part, by blocking c-Met signaling. Next, we showed that 1 mM DFMO suppressed HGF induced invasiveness of MDA-MB-435 cells in matrigel. Combination administration of DFMO with suboptimal doses of PHA-665752, a specific c-Met inhibitor, reduced invasiveness to an even greater extent than the individual treatment. These findings indicate that Src-family members, while not involved in DFMO action, promote invasiveness of breast cancer cells and their inhibition may enhance the antitumor effect of PA depletion. Our data also point to inhibition of HGF/c-Met pathway as a possible novel approach to enhancing the antitumor action of DFMO.
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PMID:Role of non-receptor and receptor tyrosine kinases (TKs) in the antitumor action of alpha-difluoromethylornithine (DFMO) in breast cancer cells. 1809 46

This in vivo study of mouse kidneys was focused on the identification of protein mediators involved in the cross-talk between two signalling pathways. One pathway was triggered by testosterone via an androgen receptor, AR, and the other induced by CB 3717/folate via HGF, and its membrane receptor c-Met. Sequential activation of these pathways leads to a drastic decrease of testosterone-induced ornithine decarboxylase, ODC, expression. We proved that CB 3717/folate-induced ODC expression is Akt-dependent. CB 3717/folate activates Akt and ERK1/2 kinases, PTEN phosphatase and also up-regulates cyclin D2 and PCNA, but decreases GSK3beta and cyclin D1 protein levels. Testosterone activation of AR induces GSK3beta and PTEN. Results of the sequential activation of the studied signalling pathways suggest that Akt, GSK3beta and possibly ERK1/2 kinases may participate in the negative cross-talk and attenuation of AR transactivity, while the involvement of PTEN and cyclin D1 seems to be doubtful.
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PMID:Antifolate/folate-activated HGF/c-Met signalling pathways in mouse kidneys-the putative role of their downstream effectors in cross-talk with androgen receptor. 1913 73