Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development. Although constitutive activation of KrasG12D in B cells induced prominent transcriptional changes that resulted in enhanced proliferation, it was not sufficient by itself to induce development of a high-grade leukemia/lymphoma. Instead, in 40% of mice, these engineered mutations promoted development of a clonal low-grade lymphoproliferative disorder resembling human extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue or lymphoplasmacytic lymphoma. Interestingly, loss of the Ink4a/Arf locus, apart from reducing the number of apoptotic B cells broadly attenuated KrasG12D-induced transcriptional signatures. However, combined Kras activation and Ink4a/Arf inactivation cooperated functionally to induce a fully penetrant, highly aggressive B-ALL phenotype resembling high-risk subtypes of human B-ALL such as BCR-ABL and CRFL2-rearranged. Ninety percent of examined murine B-ALL tumors showed loss of the wild-type Ink4a/Arf locus without acquisition of highly recurrent cooperating events, underscoring the role of Ink4a/Arf in restraining Kras-driven oncogenesis in the lymphoid compartment. These data highlight the importance of functional cooperation between mutated Kras and Ink4a/Arf loss on B-ALL.
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PMID:Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice. 2929 86

Long non-coding RNAs (lncRNAs) play an important role in various biological processes of lung adenocarcinoma (LUAD), such as immune response regulation, tumor microenvironment remodeling and genomic alteration. Nevertheless, immune-related lncRNAs and their immune and genomic alterations characteristics in LUAD samples still remain unreported. Here, using various public databases, statistic and software tools, we constructed two immune-related lncRNA clusters with different immune and genomic alterations characteristics. Notably, cluster 1 had a stronger immunosuppressive tumor microenvironment (TME) and a higher mutation frequency than cluster 2, especially the mutant genes, such as Kelch-like ECH-associated protein 1 (KEAP1) and toll like receptor 4 (TLR4). In cluster 1, both the amplified and deleted portions of copy number variation (CNV) segments were enriched and cyclin dependent kinase inhibitor 2A (CDKN2A) was significantly deleted. GSVA analysis revealed that these immune-related lncRNAs may be involved in stem cell and EMT functions. Furthermore, cluster 1 was related to worse prognosis of LUAD patients. Therefore, we constructed two immune-related and prognostic lncRNA clusters and identified their immune and genomic alterations characteristics in LUAD samples, which could well divide LUAD patients into different immune phenotypes and help to understand immune molecular mechanisms of LUAD.
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PMID:Construction of immune-related and prognostic lncRNA clusters and identification of their immune and genomic alterations characteristics in lung adenocarcinoma samples. 3244 54

A majority of mesothelioma had the wild-type p53 genotype but was defective of p53 functions primarily due to a genetic defect in INK4A/ARF region. We examined a growth suppressive activity of CP-31398 which was developed to restore the p53 functions irrespective of the genotype in mesothelioma with wild-type or mutated p53. CP-31398 up-regulated p53 levels in cells with wild-type p53 genotype but induced cell growth suppression in a p53-independent manner. In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. We investigated a combinatory effect of CP-31398 and nutlin-2a and found the combination produced synergistic growth inhibition in mesothelioma with the wild-type p53 but not with mutated p53. Western blot analysis showed that the combination increased p53 and the phosphorylation levels greater than treatments with the single agent, augmented cleavages of PARP and caspase-3, and decreased phosphorylated FAK levels. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation.
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PMID:Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype. 3246 77


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