Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCR/ABL chimeric protein plays a central role in the pathogenesis of chronic myelogenous leukemia (CML). Intensive research has elucidated many signal transduction pathways activated by BCR/ABL. However, few studies addressed BCR/ABL-dependent alterations in gene expression that may contribute to the pathobiology of CML. To additionally define such downstream genes, we performed a subtractive hybridization between cord blood (CB) CD34(+) cells transduced with an MSCV-retrovirus vector containing either enhanced green fluorescent protein (eGFP) alone or p210(BCR/ABL)-internal ribosome entry site-eGFP. Thirty-four subtracted clones expressed in p210-eGFP but not eGFP-transduced CD34(+) cells have been confirmed by Northern blot and sequenced. Fifty-nine percent represent novel proteins, and 41% are homologous to known genes. Quantitative real-time PCR analysis confirmed that 14 of 14 genes tested were also overexpressed in additional populations of p210(BCR/ABL)-transduced CB CD34(+) cells, as well as in CD34(+) cells from primary newly diagnosed CML patients versus GFP-transduced CB or samples from normal donors. Western blot analysis showed that the known sequences were also overexpressed at the protein level. Treatment of BCR/ABL(+) cells with the Abl-specific tyrosine kinase inhibitor STI571 decreased expression at the mRNA as well as protein level of some but not all of the gene products. This suggests that increased gene expression is in some cases tyrosine kinase-independent. Some of the overexpressed genes are implicated in cellular processes known to be disturbed in CML, including the mitogen-activated protein kinase or the ubiquitin pathway, whereas overexpression of other genes, including RAN and NUP98, may implicate new cellular pathways involved in CML. Additional characterization of downstream genes activated by BCR/ABL may lead to important new insights in the molecular mechanisms underlying CML and identify potentially novel therapeutic targets for CML.
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PMID:BCR/ABL-mediated increased expression of multiple known and novel genes that may contribute to the pathogenesis of chronic myelogenous leukemia. 1258 34

Mouse oocytes undergo two successive meiotic divisions to generate one large egg with two small polar bodies. The divisions are essential for preserving the maternal resources to support embryonic development. Although previous studies have shown that some small guanosine triphosphatases, such as RAC, RAN, and CDC42, play important roles in cortical polarization and spindle pole anchoring, no oocytes undergo cytokinesis when the mutant forms of these genes are expressed in mouse oocytes. Here, we show that the ADP-ribosylation factor 1 (ARF1) plays an important role in regulating asymmetric cell division in mouse oocyte meiosis. Microinjection of mRNA of a dominant negative mutant form of Arf1 (Arf1(T31N)) into fully grown germinal vesicle oocytes led to symmetric cell division in meiosis I, generating two metaphase II (MII) oocytes of equal size. Subsequently, the two MII oocytes of equal size underwent the second round of symmetric cell division to generate a four-cell embryo (zygote) when activated parthenogenetically or via sperm injection. Furthermore, inactivation of mitogen-activated protein kinase (MAPK) but not MDK (also known as MEK) has been discovered in the ARF1 mutant oocytes, and this further demonstrated that ARF1, MAPK pathway plays an important role in regulating asymmetric cell division in meiosis I. Similarly, ARF1(T31N)-expressing, superovulated MII oocytes underwent symmetric cell division in meiosis II when activation was performed. Rotation of the MII spindle for 90 degrees was prohibited in ARF1(T31N)-expressing MII oocytes. Taken together, our results suggest that ARF1 plays an essential role in regulating asymmetric cell division in female meiosis.
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PMID:ADP-ribosylation factor 1 regulates asymmetric cell division in female meiosis in the mouse. 1900 66

Histamine H(2) receptor antagonists have been reported to improve the motor symptoms of Parkinson's disease (PD) patients and to exert neuroprotective effects. In this study, we investigated the protective effects of the H(2) receptor antagonist ranitidine on rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells, focusing on mitogen-activated protein kinases (MAPKs) and caspases (CASPs)-mediated apoptotic events. Ranitidine blocked the rotenone-induced phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and P38 MAPK (P38), and promoted the phosphorylation of extracellular signal-regulated protein kinase (ERK). Ranitidine also prevented the down-regulation of B-cell CLL/lymphoma 2 (BCL2) and the up-regulation of BCL2-associated X protein (BAX) by rotenone. Furthermore, ranitidine not only attenuated rotenone-induced cleavages of CASP9, poly(ADP-ribose) polymerase-1 (PARP) and CASP3, but also suppressed CASP3 enzyme activity. These results indicate that ranitidine protects against rotenone-induced apoptosis, inhibiting phosphorylation of JNK and P38, and activation of CASPs in human dopaminergic SH-SY5Y cells.
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PMID:Protective effect of histamine H2 receptor antagonist ranitidine against rotenone-induced apoptosis. 1972 37

More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, HRAS, KRAS, and NRAS being the commonly mutated in tumors. These RAS mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, RALA and RALB, both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.
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PMID:RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer. 2919 55