Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In pro-B cell acute lymphoblastic leukemia (ALL), expression of the E2A-HLF fusion gene as a result of t(17;19)(q22;p13) is associated with poor prognosis, hypercalcemia, and hemorrhagic complications. We previously reported that the E2A-HLF fusion protein protects interleukin-3 (IL-3)-dependent lymphoid cells from apoptosis caused by cytokine starvation. Here, we report that annexin II, a surface phospholipid-binding protein and one of the proposed causes of the hemorrhagic complications of acute promyelocytic leukemia (APL), is also implicated in t(17;19)+ ALL. Annexin II was expressed at high levels in APL cells and in each of 4 t(17;19)+ leukemia cell lines, and annexin II expression was induced by enforced expression of E2A-HLF in leukemia cells. In IL-3-dependent cells, we found that annexin II expression was regulated by IL-3 mainly by Ras pathways, including Ras/phosphatidylinositol 3-kinase pathways. Moreover, E2A-HLF increased annexin II expression in IL-3-dependent cells in the absence of the cytokine. These findings indicate that E2A-HLF induces annexin II by substituting for cytokines that activate downstream pathways of Ras.
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PMID:Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. 1507 Jul 1

The active form of 1,25-dihydroxyvitamin D(3) prevents neuronal damage in vitro and in vivo , however, it induces also hypercalcemia and hyperphosphatemia. Side-chain-modified analogues of 1,25-dihydroxyvitamin D(3), which show low calcemic activity, may be potentially useful in the treatment of some neurodegenerative diseases. Previously, we have found that PRI-2191 more potently than 1,25-dihydroxyvitamin D(3) protects human neuroblastoma (SH-SY5Y) cells against hydrogen-peroxide-induced toxicity. In the present study, we evaluated effects of two other 1,25-dihydroxyvitamin D(3) analogues - PRI-1890 and PRI-1901 on the neuronal degeneration in the same cell model. In line with the previous study, 24-h incubation with hydrogen peroxide (0.5 mM) was toxic to cells, as evidenced by an enhanced efflux of lactate dehydrogenase into the culture medium, and these effects were prevented by PRI-1890 and PRI-1901 at concentration of 5, 50 and 500 nM. Comparing the neuroprotective effects of secosteroids, we found that all three analogues were efficient at lower concentration than 1,25-dihydroxyvitamin D(3) and among them the PRI-2191 showed the most evident concentration-dependent effect. In the second part of this study, an involvement of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K), kinases which play a crucial role in neurodegenerative processes, in neuroprotective action of 1,25 dihydroxyvitamin D(3) and its the most potent analogue PRI-2191 has been investigated. The inhibitor of c-Jun N-terminal kinase (JNK)-MAPK (SP600125, 1 microM), inhibitor of p38-MAPK (SB-203580, 1 and 10 microM) and inhibitor of extracellular signal-regulated kinase (ERK)-MAPK (PD-98059, 15 and 30 microM) attenuated the hydrogen peroxide-induced toxicity. Moreover, PD-98059 (30 microM) enhanced neuroprotective effects of 1,25 dihydroxyvitamin D(3) but not that of PRI-2191. In contrast, the inhibitor of PI3-K (wortmannin, 10, 100 nM) did not affect hydrogen peroxide-induced cell damage itself, however, it significantly antagonized the effect of PRI-2191. On the other hand, wortmannin did not affect the neuroprotective effects of 1,25 dihydroxyvitamin D(3) This suggests that the activation of PI3-K/Akt signaling pathway plays an important role in the mechanism of inhibitory action of PRI-2191 on hydrogen peroxide-evoked toxicity in SH-SY5Y cells. Furthermore, these data point to differential involvement of ERK-MAPK and PI3-K in neuroprotective effects of 1,25 dihydroxyvitamin D(3) and its low-calcemic analogue - PRI-2191.
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PMID:Involvement of PI3-K in neuroprotective effects of the 1,25-dihydroxyvitamin D3 analogue - PRI-2191. 1722 May 48