Browsing by Subject "TP53"

Now showing 1 - 4 of 4
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    p53 involvement in clonal hematopoiesis of indeterminate potential
    (Wolters Kluwer, 2019-05) Chen, Sisi; Liu, Yan; Pediatrics, School of Medicine
    Purpose of review Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and occurs when a single mutant hematopoietic stem cell (HSC) contributes to a significant clonal proportion of mature blood lineages. Somatic mutations in the TP53 gene, which encodes the tumor suppressor protein p53, rank in the top five among genes that were mutated in CHIP. This review focuses on mechanisms by which mutant p53 promotes CHIP progression and drives the pathogenesis of hematological malignancies, including myelodysplastic syndromes, and acute myeloid leukemia. Recent findings TP53 was frequently mutated in individuals with CHIP. Although clinical studies suggest that expansion of HSCs with TP53 mutations predisposes the elderly to hematological neoplasms, there is a significant gap in knowledge regarding the mechanisms by which TP53 mutations promote HSC expansion. Recent findings suggest that several cellular stressors, including hematopoietic transplantation, genotoxic stress, and inflammation, promote the expansion of HSCs with TP53 mutations. Further, TP53 mutations identified in CHIP cooperate with genetic and/or epigenetic changes in leukemogenesis. Summary TP53 mutations identified in CHIP are associated with increased risks of de novo and therapy-related hematological neoplasms. Thus, targeting mutant p53 and related pathways holds great potential in preventing CHIP progression and treating hematological malignancies.
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    Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers
    (BioMed Central, 2019-08-05) Hancock, Bradley A.; Chen, Yu-Hsiang; Solzak, Jeffrey P.; Ahmad, Mufti N.; Wedge, David C.; Brinza, Dumitru; Scafe, Charles; Veitch, James; Gottimukkala, Rajesh; Short, Walt; Atale, Rutuja V.; Ivan, Mircea; Badve, Sunil S.; Schneider, Bryan P.; Lu, Xiongbin; Miller, Kathy D.; Radovich, Milan; Surgery, School of Medicine
    BACKGROUND: Approximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development. METHODS: We assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes. RESULTS: Analysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2. CONCLUSIONS: We conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.
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    Roles of alternative splicing in modulating transcriptional regulation
    (BMC, 2017-10-03) Li, Jin; Wang, Yang; Rao, Xi; Wang, Yue; Feng, Weixing; Liang, Hong; Medical and Molecular Genetics, School of Medicine
    Background The ability of a transcription factor to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms. Alternative splicing can modulate gene function by adding or removing certain protein domains, and therefore affect the activity of protein. Reverse engineering of gene regulatory networks using gene expression profiles has proven valuable in dissecting the logical relationships among multiple proteins during the transcriptional regulation. However, it is unclear whether alternative splicing of certain proteins affects the activity of other transcription factors. Results In order to investigate the roles of alternative splicing during transcriptional regulation, we constructed a statistical model to infer whether the alternative splicing events of modulator proteins can affect the ability of key transcription factors in regulating the expression levels of their transcriptional targets. We tested our strategy in KIRC (Kidney Renal Clear Cell Carcinoma) using the RNA-seq data downloaded from TCGA (the Cancer Genomic Atlas). We identified 828of modulation relationships between the splicing levels of modulator proteins and activity levels of transcription factors. For instance, we found that the activity levels of GR (glucocorticoid receptor) protein, a key transcription factor in kidney, can be influenced by the splicing status of multiple proteins, including TP53, MDM2 (mouse double minute 2 homolog), RBM14 (RNA-binding protein 14) and SLK (STE20 like kinase). The influenced GR-targets are enriched by key cancer-related pathways, including p53 signaling pathway, TR/RXR activation, CAR/RXR activation, G1/S checkpoint regulation pathway, and G2/M DNA damage checkpoint regulation pathway. Conclusions Our analysis suggests, for the first time, that exon inclusion levels of certain regulatory proteins can affect the activities of many transcription factors. Such analysis can potentially unravel a novel mechanism of how splicing variation influences the cellular function and provide important insights for how dysregulation of splicing outcome can lead to various diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0465-6) contains supplementary material, which is available to authorized users.
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    Tip110/SART3 regulates IL-8 expression and predicts the clinical outcomes in melanoma
    (Biomed Central, 2018-08-17) Timani, Khalid Amine; Győrffy, Balázs; Liu, Ying; Mohammad, Khalid S.; He, Johnny J.; Medicine, School of Medicine
    Tip110, an important regulator of several oncogenic proteins, was significantly downregulated in human metastatic melanoma cells exposed to a hypoxic condition. Therefore, in this study, we set to determine whether differential expression of Tip110 could be an important indicator for melanoma tumorigenesis and metastasis. We found that in melanoma, but not in other cancer types, Tip110 knockdown enhanced significant expression and secretion of IL-8 and melanoma cells invasions. This induction was further potentiated under hypoxia and by inflammatory cytokine and found independent of TNF-α autocrine signaling. We further showed that Tip110 knockdown-mediated IL-8 induction involved IL-8 mRNA stability. Furthermore, the transcriptomic profiling data and survival from 455 melanoma patients demonstrated that the correlation between Tip110 expression and the clinical outcomes in melanoma was stage-dependent. These findings uncover important roles of Tip110 in melanoma tumorigenesis and metastasis through regulation of IL-8 and hope to provide new clues for future therapeutic strategies.