Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p73 is a novel member of the p53 family of tumor suppressor proteins which is involved in cellular differentiation, tumor suppression, and the response to genotoxic stress. The molecular mechanisms regulating p73 activity are still poorly understood. Recently, p73 was found to be a target of the enzymatic activity of c-Abl, a non-receptor tyrosine kinase that potently activated in response to DNA damage. Here, we present evidence that c-Abl induces the phosphorylation of p73 in threonine residues adjacent to prolines, and that the p38 MAP kinase pathway mediates this response. Furthermore, we found that activation of p38 is sufficient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38. These findings indicate that members of the MAP kinases superfamily of signaling molecules can regulate p73, and support a role for the p38 MAP kinase in a novel biochemical pathway by which c-Abl regulates this p53-related molecule.
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PMID:Regulation of p73 by c-Abl through the p38 MAP kinase pathway. 1184 Mar 43

Phosphorylation of the p53 tumor suppressor protein is one of the key regulatory steps in its activation process. Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation, but the signaling pathway mediating UV-induced phosphorylation is unknown. Here, we determined the role of MAP kinases in UVB-induced phosphorylation and found that JNKs are directly involved in the phosphorylation of p53 at serine 20. In a mouse JB6 epidermal cell line, dominant negative JNK1 abrogated UVB-induced phosphorylation of p53 at serine 20, whereas dominant negative p38 kinase or its inhibitor, SB202190, partially attenuated the phosphorylation. In contrast, dominant negative ERK2 or the MEK1 inhibitor, PD98059, had no effect on p53 phosphorylation at serine 20. Importantly, UVB-activated or active recombinant JNK1/2, or the p38 kinase downstream target, MAPKAPK-2, but not ERKs or p38 kinase, phosphorylated p53 at serine 20 in vitro. Furthermore, phosphorylation of p53 at serine 20 by UVB-activated JNKs and UVB-induced p53-dependent transcriptional activity were suppressed in Jnk1 or Jnk2 knockout (Jnk1(-/-) or Jnk2(-/-)) cells. Additionally, Jnk1(-/-), Jnk2(-/-), and p53-deficient (p53(-/-)) cells, as well as re-introduction of a p53 mutant with substitution of serine 20 to alanine into p53(-/-) cells, were defective for UVB-induced apoptosis. These findings strongly suggest that JNKs are the major direct signaling mediators of UVB-induced p53 phosphorylation at serine 20.
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PMID:Role of MAP kinases in UVB-induced phosphorylation of p53 at serine 20. 1189 87

Drm/Gremlin, a member of the Dan family of BMP antagonists, is known to function in early embryonic development, but is also expressed in a tissue-specific fashion in adults and is significantly downregulated in transformed cells. In this report, we demonstrate that overexpression of Drm in the tumor-derived cell lines Daoy (primitive neuroectodermal) and Saos-2 (osteoblastic), either under ecdysone-inducible or constitutive promoters, significantly inhibits tumorigenesis. Furthermore, Drm overexpression in these cells increases the level of p21(Cip1) protein and reduces the level of phosphorylated p42/44 MAP kinase. Finally, our data indicate that Drm can induce p21(Cip1) transcriptionally via a novel pathway that is independent of p53 and the p38 and p42/44 MAP kinases. These results provide evidence that Drm can function as a novel transformation suppressor and suggest that this may occur through its affect on the levels of p21(Cip1) and phosphorylated p42/44 MAPK.
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PMID:Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. 1213 12

Previously we showed that cardiac fibroblasts are cellular targets of estrogen and that there are significant differences in proliferative response of male and female cardiac fibroblasts under hypoxia, a condition of myocardial ischemia. Here, we tested the hypothesis that signaling pathways that control cell cycle progression and apoptosis in cardiac fibroblasts may be activated in a gender-specific manner. Cardiac fibroblasts from adult, age-matched male and female rat heart were exposed to hypoxia (2% O2) and normoxia. Western analysis of cell lysate was used to compare the level of basal and hypoxia-induced expression of signal transduction proteins, known to control cell cycle progression and cell death. Hypoxia led to significant activation of MAP (mitogen-activated protein) kinase and Jun kinase pathways, as shown by phosphorylated extracellular signal-regulated kinase (ERK1/2) and Jun kinase isotypes in male cells but this effect was modest in female cells. Male cells expressed higher levels of basal expression for transcription factors c-jun and NF-kB as well as the inhibitor of NF-kB (lk-B). Although hypoxia did not induce changes in the level of c-Jun in either cell type, it moderately increased the level of NF-kB in male cells but led to its decrease in female cells. Basal and hypoxia-induced expression of cyclin D1, c-fos, and PCNA seemed to be comparable in both male and female cells. However, hypoxia-induced activation of cyclin B1, which occurred in both cells, was stronger in female cells. Basal expression of apoptosis-associated transcription factor, p53, was comparable in both cells. However, under hypoxia, there was an increase in the p53 level only in female cells. Although female cells showed higher basal expression for survival-associated protein, Bcl-2, the level of this protein remained unchanged under hypoxia in both cells. Together, these data demonstrate differences in basal and hypoxia-induced expression of proteins with an established role in cell cycle progression and apoptosis in male and female cardiac fibroblasts. These differences may further point to gender-related differences in signal transduction pathways that control the proliferative response of those cells under hypoxia.
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PMID:Gender-related differences in basal and hypoxia-induced activation of signal transduction pathways controlling cell cycle progression and apoptosis, in cardiac fibroblasts. 1237 61

Chemoprevention is a promising approach to control human cancer. Resveratrol has been shown to have a potent chemopreventive effect in multiple carcinogenesis models. However, the precise mechanism explaining its anti-carcinogenic effect is not clear. This review summarizes recent studies from our laboratory on the mechanisms of resveratrol's effects. In JB6 cells, resveratrol was found to induce apoptosis and inhibit tumor promoter-induced cell transformation. We also found that resveratrol-induced activation of p53 and resveratrol-induced apoptosis occurred through a p53-dependent pathway. The MAP kinases, ERKs, JNKs, or p38 kinases, are involved in resveratrol-induced activation of p53 and apoptosis.
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PMID:Molecular mechanism of the chemopreventive effect of resveratrol. 1262 12

To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent and -independent pathways, regulated by MAP kinases, which likely play a protective role.
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PMID:Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid. 1465 60

The p53 tumor suppressor protein exerts its growth inhibitory activity by activating and interacting with diverse signaling pathways. As a downstream target, p53 protein is phosphorylated and activated by a number of protein kinases in response to stressful stimuli. As an upstream activator, activated p53 acts as a transcription factor to induce and/or suppress a number of genes whose expression leads to the activation of diverse signaling pathways. p53 protein can also interact with a number of proteins, resulting in an increase or decrease in p53 activity itself. The activation of p53 leads to many outcomes in cells, including cell cycle arrest and apoptosis. It has become clear that the p53 protein can functionally interact with the mitogen-activated protein kinase (MAPK) pathways, including the stress-activated protein kinase [SAPK/c-Jun N-terminal protein kinase (JNK)], the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal related kinase (ERK). Upon exposure to stressful stimuli, MAP kinases phosphorylate and activate p53, leading to p53-mediated cellular responses. Recent studies have suggested a role of p53 as an upstream activator to regulate MAPK signaling via the transcriptional activation of members of the dual specificity phosphatase family. Because both the p53 and MAPK signaling pathways are altered in the majority of human tumors, understanding their functional interaction may provide new insights into the deregulated cell proliferation and survival that is characteristic of cancer.
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PMID:The functional interactions between the p53 and MAPK signaling pathways. 1476 89

Mammalian cells undergo programmed cell death by orchestrated interactions involving multiple independent pathways. At least one of them, the p53-dependent pathway is commonly compromised in Burkitt's lymphoma (BL) cell lines. Differences in the integrity of this pathway in various BL cell lines have made them useful experimental models in understanding response to standard or novel antitumor drugs vis-a-vis the p53 pathway. Non-p53-dependent loss of apoptotic regulation also contributes to the genesis and/or progression of lymphomas and it is possible that BL cell lines also represent these models. We have characterized the expression of multiple apoptotic proteins in a panel of BL cell lines and describe cell lines with loss of cIAP1, cIAP2, Bax, Bak, Bcl-Xs and p38 MAP-kinase. This data should make this panel of cell lines a useful screening system for testing novel apoptotic inducers.
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PMID:Differences in the expression of apoptotic proteins in Burkitt's lymphoma cell lines: potential models for screening apoptosis-inducing agents. 1510 24

The proto-oncogene, bcl-2, has various functions besides its role in protecting cells from apoptosis. One of the functions is to regulate expression of other genes. Previous studies have demonstrated that Bcl-2 regulates activities of several important transcription factors including NF-kappaB and p53, and also their downstream genes. In our recent studies, we reported that Bcl-2 substantially downregulates expression of the endogenous alphaB-crystallin gene through modulating the transcriptional activity of lens epithelium-derived growth factor (LEDGF). In the present communication, we report that human Bcl-2 can positively regulate expression of the proto-oncogenes c-jun and c-fos. Moreover, it enhances the DNA binding activity and transactivity of the activating protein-1 (AP-1). Furthermore, we present evidence to show that Bcl-2 can also activate both ERK1 and ERK2 MAP kinases. Inhibition of the activities of these kinases or the upstream activating kinases by pharmacological inhibitors or dominant-negative mutants abolishes the Bcl-2-mediated regulation of AP-1, LEDGF and their downstream genes. Together, our results demonstrate that through activation of the ERK kinase signaling pathway, Bcl-2 regulates the transcriptional activities of multiple transcription factors, and hence modulates the expression of their downstream genes. Thus, our results provide a mechanism to explain how Bcl-2 may regulate expression of other genes.
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PMID:Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes. 1532 76

Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.
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PMID:Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma. 1550 68


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