Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Triplex DNA is implicated in a wide range of biological activities, including regulation of gene expression and genomic instability leading to cancer. The tumor suppressor p53 is a central regulator of cell fate in response to different type of insults. Sequence and structure specific modes of DNA recognition are core attributes of the p53 protein. The focus of this work is the structure-specific binding of p53 to DNA containing triplex-forming sequences in vitro and in cells and the effect on p53-driven transcription. This is the first DNA binding study of full-length p53 and its deletion variants to both intermolecular and intramolecular T.A.T triplexes. We demonstrate that the interaction of p53 with intermolecular T.A.T triplex is comparable to the recognition of CTG-hairpin non-B DNA structure. Using deletion mutants we determined the C-terminal DNA binding domain of p53 to be crucial for triplex recognition. Furthermore, strong p53 recognition of intramolecular T.A.T triplexes (H-DNA), stabilized by negative superhelicity in plasmid DNA, was detected by competition and immunoprecipitation experiments, and visualized by AFM. Moreover, chromatin immunoprecipitation revealed p53 binding T.A.T forming sequence in vivo. Enhanced reporter transactivation by p53 on insertion of triplex forming sequence into plasmid with p53 consensus sequence was observed by luciferase reporter assays. In-silico scan of human regulatory regions for the simultaneous presence of both consensus sequence and T.A.T motifs identified a set of candidate p53 target genes and p53-dependent activation of several of them (ABCG5, ENOX1, INSR, MCC, NFAT5) was confirmed by RT-qPCR. Our results show that T.A.T triplex comprises a new class of p53 binding sites targeted by p53 in a DNA structure-dependent mode in vitro and in cells. The contribution of p53 DNA structure-dependent binding to the regulation of transcription is discussed.
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PMID:p53 Specifically Binds Triplex DNA In Vitro and in Cells. 2790 75

Ribociclib (Kisqali) for HR+/HER2- advanced or metastatic breast cancer in postmenopausal women; safinamide (Xadago) as adjunctive treatment for patients with Parkinson's disease; and avelumab (Bavencio) for metastatic Merkel cell carcinoma.
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PMID:Pharmaceutical Approval Update. 2857 22

Neoadjuvant immune checkpoint inhibition is gaining ground as a treatment strategy for early-stage, operable cancers. The list of potentially responsive tumor types now includes Merkel cell carcinoma; recent findings from an arm of the I-SPY2 trial also support the utility of this approach in HER2-negative breast cancer.
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PMID:Neoadjuvant Immunotherapy: Making Strides. 3246 41

Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm of neuroendocrine carcinoma of the skin. About 80% of the MCC occurs due to Merkel cell polyomavirus (MCPyV) and 20% of the tumors usually occur due to severe UV exposure which is a more aggressive type of MCC. It tends to have an increased incidence rate among elderly and immunosuppressed individuals. On therapeutic level, sub-classification of MCC through molecular subtyping has emerged as a promising technique for MCC prognosis. In current study, two consistent distinct molecular subtypes of MCCs were identified using gene expression profiling data. Subtypes I MCCs were associated with spliceosome, DNA replication and cellular pathways. On the other hand, genes overexpressed in subtype II were found active in TNF signalling pathway and MAPK signalling pathway. We proposed different therapeutic targets based on subtype specificity, such as PTCH1, CDKN2A, AURKA in case of subtype I and MCL1, FGFR2 for subtype II. Such findings may provide fruitful knowledge to understand the intrinsic subtypes of MCCs and the pathways involved in distinct subtype oncogenesis, and will further advance the knowledge in developing a specific therapeutic strategy for these MCC subtypes.
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PMID:Gene expression profile identifies distinct molecular subtypes and potential therapeutic genes in Merkel cell carcinoma. 3277 71


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