Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimeric G proteins have emerged as important regulators of membrane trafficking. To explore a role for G beta gamma in endosome fusion, we have taken advantage of beta-adrenergic receptor kinase (beta ARK), an enzyme translocated to membranes by interaction with G beta gamma. The COOH terminus of beta ARK (beta ARKct) has a G beta gamma-binding domain which blocks some G beta gamma-mediated processes. We found that beta ARKct and peptide G, a peptide derived from beta ARKct, inhibit in vitro endosome fusion. Interestingly, peptide G and ARF share sequence similarity. Peptide G and beta ARKct reversed ARF-mediated inhibition of endosome fusion and blocked ARF binding to membranes. Using an ARF fusion protein, we show that both G beta gamma and G alpha s interact with the small GTPase ARF, an interaction that is regulated by nucleotide binding. We conclude that G proteins may participate in the regulation of vesicular trafficking by directly interacting with ARF, a cytosolic factor required for transport.
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PMID:Heterotrimeric G proteins interact with the small GTPase ARF. Possibilities for the regulation of vesicular traffic. 759 75

Normal human fibroblasts have been shown to undergo a p16(Ink4a)-associated senescence-like growth arrest in response to sustained activation of the Ras/Raf/MEK/ERK pathway. We noted a similar p16(Ink4a)-associated, senescence-like arrest in normal human astrocytes in response to expression of a conditional form of Raf-1. While HPV16 E7-mediated functional inactivation of the p16(Ink4a)/pRb pathway in astrocytes blocked the p16(Ink4a)-associated growth arrest in response to activation of Raf-1, it also revealed a second p21(Cip1)-associated, senescence-associated, beta-galactosidase-independent growth arrest pathway. Importantly, the p21(Cip1)-associated pathway was present not only in normal astrocytes but also in p53-, p14(ARF)-, and p16(Ink4a)/pRb-deficient high grade glioma cells that lacked the p16(Ink4a)-dependent arrest mechanism. These results suggest that normal human cells have redundant arrest pathways, which can be activated by Raf-1, and that even tumors that have dismantled p16(Ink4a)-dependent growth arrest pathways are potentially regulated by a second p21(Cip1)-dependent growth arrest pathway.
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PMID:Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation. 1127 20

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.
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PMID:Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. 1241 39

Pleomorphic xanthoastrocytoma (PXA) is a rare, usually well-circumscribed and superficially located neoplasm that preferentially arises in the cerebral cortex of children and young adults. The molecular aberrations that are associated with these tumors have not been studied systematically so far. We here report on a molecular genetic analysis of 62 PXAs (46 PXAs of World Health Organization [WHO] grade II and 16 PXAs with anaplastic features) for alterations of 5 candidate genes known to be frequently aberrant in diffusely infiltrating astrocytic gliomas, i.e. TP53, CDKN2A (p16(INK4a)), CDK4, MDM2, and EGFR. Only 3 PXAs (5%) carried a TP53 mutation. None of the 62 PXAs had lost both copies of the CDKN2A gene. The CDK4, MDM2, or EGFR genes were not amplified in any of the tumors. Fourteen PXAs were additionally analyzed for loss of heterozygosity (LOH) at microsatellite markers located on the chromosomes/chromosomal arms 1, gp, 9p, 10, 17, 19q, and 22q. Two PXAs (14%) had LOH at all informative markers on 9p, while 1 PXA demonstrated an interstitial area of allelic imbalance between D22S533 and D22S417 at 22q11.2-q13.3. Further analysis of 10 PXAs for inactivation of the CDKN2A. p14(ARF), and CDKN2B (p15(INK4b)) genes on 9p21 did not reveal any homozygous deletion, mutation, promoter hypermethylation, or complete loss of mRNA expression. Taken together, our results indicate that the chromosomal and genetic aberrations in PXAs are different from those typically associated with the diffusely infiltrating astrocytic and oligodendroglial gliomas. These genetic differences likely contribute to the more favorable behavior of PXAs and may be helpful for the molecular differential diagnosis of cerebral gliomas.
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PMID:Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are rare or absent in pleomorphic xanthoastrocytomas. 1248 72

During malignant transformation in skin, epidermal keratinocytes (KCs) frequently acquire the capacity to by-pass cellular senescence, a response that normally limits their unrestricted proliferation. Despite growing interest in the role for senescence during aging of skin and cutaneous carcinogenesis, little is known regarding regulation of three proteins encoded by the INK4a/ARF locus (p12, p14(ARF), p16) in KCs. In this study, several molecular pathways are explored using cultured KCs and KCs freshly isolated from psoriatic plaques. p16 and p14(ARF) are predominantly expressed spontaneously when foreskin-derived early-passage KCs undergo confluency-induced premature senescence. Induction of p14(ARF) on confluency occurred with low E2F-1 levels. Suspension of KCs in methylcellulose induced p12 expression. Addition of various cytokines (interferon-gamma, tumor necrosis factor-alpha) or a phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] only induced p16, but not p14(ARF). Confluent KCs up-regulated Ras activity and the downstream signaling involving ERK. Addition of MAPK inhibitor blocked cytokine and TPA-induced p16 expression. Confluency and interferon-gamma induced premature senescence and p16 expression was linked to induction of the transcription factor Egr-1. KCs derived from chronic psoriatic plaques were characterized by enhanced p16, p14(ARF), and p12 expression accompanied by elevated Egr-1 levels. These results demonstrate that multiple and highly divergent stimuli can trigger the senescent checkpoint in human KCs with differential regulation of p16, p14(ARF), and p12. Although abnormal mitogenic signaling by oncogenic Ras is generally cited as being responsible for induction of premature senescence, our findings indicate that a broader perspective is warranted, to include confluency and cytokine-/TPA-induced pathways for KCs.
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PMID:Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes. 1250 99

Bladder cancer is the most common urinary tumors in China. Carcinogenesis of bladder is a multistep process. Accumulation of abnormal genotypes in a long period leads to malignant phenotypes. The genes associated with bladder carcinogenesis include oncogenes (such as H-ras, FGFR3, erbB2, CCND1, mdm2), tumor suppressor genes (such as INK4A/ARF, Rb, TP53, PTEN, TSC1, PTCH, DBCCR1), and DNA mismatch repair genes, etc. In this review, the authors discussed the recent research advances on the genes associated with bladder carcinoma.
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PMID:[Research advances on bladder cancer associated genes]. 1256 47

DDR1, discoidin domain receptor 1, belongs to a subfamily of tyrosine kinase receptors with an extracellular domain homologous to Dictyostellium discoideum protein discoidin 1. We showed that DDR1 is a direct p53 transcriptional target, and that DNA damage induced a p53-dependent DDR1 response associated with activation of its tyrosine kinase. We further demonstrated that DDR1 activated the MAPK cascade in a Ras-dependent manner. Whereas levels of p53, phosphoserine-15 p53, p21, ARF and Bcl-X(L) were increased in response to exogenous overexpression of activated DDR1, dominant-negative DDR1 inhibited irradiation-induced MAPK activation and p53, phosphoserine-15 p53, as well as induced p21 and DDR1 levels, suggesting that DDR1 functions in a feedforward loop to increase p53 levels and at least some of its effectors. Nonetheless, inhibition of DDR1 function resulted in strikingly increased apoptosis of wild-type p53-containing cells in response to genotoxic stress through a caspase-dependent pathway. These results strongly imply that this p53 response gene must predominately act to alleviate the adverse effects of stress induced by p53 on its target cell.
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PMID:p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. 1262 22

Both genetic and environmental factors confer a significantly increased risk for cutaneous melanoma. This review discusses hereditary predisposition to the disease, focusing on the high-penetrance candidate genes INK4A/ARF and CDK4, and on pathogenetic mechanisms of mutations in those genes. As known mutations account for approximately 25 to 40% of melanoma families reported to date, it is clear that other melanoma genes and other mechanisms underlying predisposition remain to be discovered. Low penetrance susceptibility genes such as melanocortin 1 receptor and their modifying effect, also in concert with UV radiation, are likely to be implicated. Recent reports on a new candidate locus on chromosome 1p22 and somatic mutations in genes of the RAS-RAF-ERK signalling pathway raise interesting questions for further investigation.
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PMID:Genetics of melanoma susceptibility. 1473 79

Gliomas are the most common primary neoplasm of the brain. Unfortunately, they are often refractory to treatment and portend a poor prognosis. However, recent discoveries have shed light on the molecular events driving glioma growth, including abnormalities of three major molecular pathways: extracellular growth factors and their receptors (eg, EGF/EGFR and PDGF/PDGFR), signal transduction cascades (eg, RAS and AKT), and cell proliferation controls (eg, INK4A-ARF). Each of these abnormalities is described in detail. Efforts to inhibit abnormally activated pathways are underway through multi-institutional clinical trials.
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PMID:Molecular biology of gliomas. 1510 49

The INK4a/ARF locus on chromosome 9p21 is one of the important defenses against tumor development and engages both the Rb and the p53 tumor suppressor pathways through its capacity to encode two distinct proteins, p16(INK4a) and p14(ARF). Despite controversial reports, the body of present data suggests that tumor suppressors p16(INK4a) and p14(ARF) are targets of in-activation in GEP-NETs. Moreover, tumor type-specific aberrant p16(INK4a) silencing appears to be associated with advanced tumor stage and may function as a predictor of patients' outcome after surgical resection. Since conventional histological and biochemical assessment are limited with respect to predicting GEP-NET behavior or outcome, methylation profiles including INK4a/ARF might offer a tool to refine future diagnosis and therapeutic management of GEP-NET patients.
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PMID:Implication of the INK4a/ARF locus in gastroenteropancreatic neuroendocrine tumorigenesis. 1515 47


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