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【作者单位】
="Department of Otorhinolaryngology Baylor College of MedicineDepartment of Molecular and Cellular Biology Baylor College of MedicineHuffington Center on Aging Baylor College of Medicine"
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The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-β s...
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The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-β signaling through its association with the Smad proteins. However, new studies suggest that SKI plays additional roles not only inside but also outside the nucleus. In normal melanocytes and primary non-invasive melanomas, SKI localizes predominantly in the nucleus, whereas in primary invasive melanomas SKI displays both nuclear and cytoplasmic localization. Intriguingly, metastatic melanoma tumors display nuclear and cytoplasmic or predominantly cytoplasmic SKI distribution. Cytoplasmic SKI is functional, as it associates with Smad3 and prevents its nuclear localization mediated by TGF-β. SKI can also function as a transcriptional activator, targeting the β -catenin pathway and activating MITF and NrCAM, two proteins involved in survival, migration and invasion. Intriguingly, SKI appears to live a dual life, one as a tumor suppressor and another as a transforming protein. Loss of one copy of mouse ski increases susceptibility to tumorigenesis in mice, whereas its overexpression is associated with cancer progression of human melanoma, esophageal, breast and colon. The molecular reasons for such dramatic change in SKI function appear to result from new acquired activities. In this review, we discuss the mechanisms by which SKI regulates crucial pathways involved in the progression of human malignant melanoma.
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We report on the linear and nonlinear dielectric properties of budding yeast (S. cerevisiae) cells, one strain of which has been genetically modified to express prestin. This motor protein plays a crucial role in the large electro...
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We report on the linear and nonlinear dielectric properties of budding yeast (S. cerevisiae) cells, one strain of which has been genetically modified to express prestin. This motor protein plays a crucial role in the large electromotility exhibited by the outer hair cells of mammalian inner ears. Live cell suspensions exhibit enormous dielectric responses, which can be used to probe metabolic activity, membrane potential, and other properties. The aims of this study are: (1) to compare the dielectric responses of organisms expressing prestin from those of control specimens, and (2) ultimately to further develop dielectric response as a tool to study live cells, proteins, and lipids.
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Nuclear metastasis-associated 1(MTA1) protein is an estrogen receptor co-repressor that regulates transcription via chromatin remodeling, and MTA1 messenger ribonucleic acid (mRNA) levels are elevated in several kinds of locally a...
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Nuclear metastasis-associated 1(MTA1) protein is an estrogen receptor co-repressor that regulates transcription via chromatin remodeling, and MTA1 messenger ribonucleic acid (mRNA) levels are elevated in several kinds of locally advanced and metastatic tumors relative to non-metastatic tumors. Previous studies in our laboratory mapped MTA1 into a region showing significantly lower LOH (loss of heterozygosity) in primary breast cancers with metastases compared to node-negative tumors, suggesting that epigenetic alterations of MTA1 affect metastatic potential. The present study examined immunohistochemical expression of the MTA1 protein in treated and untreated primary human breast cancers to study the relationship between MTA1 expression and clinical outcome. Node-negative tumors that overexpress MTA1 protein had recurrence risks similar to node-positive tumors. In multivariate analysis of untreated node-negative tumors, highest expression of MTA1 was associated with increased relapse risk (hazard ratio (HR)=2.72, p=0.0003 for multivariate analysis). Tamoxifen and/or anthracylcene-based chemotherapies eliminated all MTA1 associations with clinical outcome, suggesting MTA1 overexpression predicts early disease relapse, but sensitizes breast tumors to systemic therapies.
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The governors of a number of states, including New York and New Jersey, recently imposed 21-day quarantines on health care workers returning to the United States from regions of the world where they may have cared for patients wit...
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The governors of a number of states, including New York and New Jersey, recently imposed 21-day quarantines on health care workers returning to the United States from regions of the world where they may have cared for patients with Ebola virus disease. We understand their motivation for this policy - to protect the citizens of their states from contracting this often-fatal illness. This approach, however, is not scientifically based, is unfair and unwise, and will impede essential efforts to stop these awful outbreaks of Ebola disease at their source, which is the only satisfactory goal. The governors' action is like driving a carpet tack with a sledgehammer: it gets the job done but overall is more destructive than beneficial.
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Chromatin immunoprecipitation studies have mapped protein occupancies at many genomic loci. However, a detailed picture of the complexity of coregulators (CoRs) bound to a defined enhancer along with a transcription factor is miss...
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Chromatin immunoprecipitation studies have mapped protein occupancies at many genomic loci. However, a detailed picture of the complexity of coregulators (CoRs) bound to a defined enhancer along with a transcription factor is missing. To address this,we used biotin-DNA pull-down assays coupled with mass spectrometry-immunoblotting to identify at least 17 CoRs from nuclear extracts bound to 17β-estradiol (E2)-liganded estrogen receptor-α on estrogen response elements (EREs). Unexpectedly, these complexes initially are biochemically stable and contain certain atypical corepressors. Addition of ATP dynamically converts these complexes to an "activated" state by phosphorylation events, primarily mediated by DNA-dependent protein kinase. Importantly, a "natural" ERE-containing enhancer and nucleosomal EREs recruit similar complexes. We further discovered the mechanism whereby H3K4me3 stimulates ERα-mediated transcription as compared with unmodified nucleosomes. H3K4me3 templates promote specific CoR dynamics in the presence of ATP and AcCoA, as manifested by CBP/p300 and SRC-3 dismissal and SAGA and TFIID stabilization/recruitment.
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Twist1 promotes epithelial-mesenchymal transition, invasion, metastasis, stemness, and chemotherapy resistance in cancer cells and thus is a potential target for cancer therapy. However, Twist1-null mice are embryonic lethal, and ...
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Twist1 promotes epithelial-mesenchymal transition, invasion, metastasis, stemness, and chemotherapy resistance in cancer cells and thus is a potential target for cancer therapy. However, Twist1-null mice are embryonic lethal, and people with one Twist1 germline mutant allele develop Saethre-Chotzen syndrome; it is questionable whether Twist1 can be targeted in patients without severe adverse effects. We found that Twist1 is expressed in several tissues, including fibroblasts of the mammary glands and dermal papilla cells of the hair follicles. We developed a tamoxifen-inducible Twist1 knockout mouse model; Twist1 knockout in 6-week-old female mice did not affect mammary gland morphogenesis and function during pregnancy and lactation. In both males and females, the knockout did not influence body weight gain, heart rate, or total lean and fat components. The knockout also did not alter blood pressure in males, although it slightly reduced blood pressure in females. Although Twist1 is not cyclically expressed in dermal papilla cells, knockout of Twist1 at postnatal day 13 (when hair follicles have developed) drastically extended the anagen phase and accelerated hair growth. These results indicate that Twist1 is not essential for maintaining an overall healthy condition in young and adult mice and that loss of function facilitates hair growth in adulthood, supporting Twist1 as a preferential target for cancer therapy.
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High content screening (HCS) has emerged an important tool for drug discovery because it combines rich readouts of cellular responses in a single experiment. Inclusion of cell cycle analysis into HCS is essential to identify clini...
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High content screening (HCS) has emerged an important tool for drug discovery because it combines rich readouts of cellular responses in a single experiment. Inclusion of cell cycle analysis into HCS is essential to identify clinically suitable anticancer drugs that disrupt the aberrant mitotic activity of cells. One challenge for integration of cell cycle analysis into HCS is that cells must be chemically synchronized to specific phases, adding experimental complexity to high content screens. To address this issue, we have developed a rules-based method that utilizes mitotic phosphoprotein monoclonal 2 (MPM-2) marker and works consistently in different experimental conditions and in asynchronous populations. Further, the performance of the rules-based method is comparable to established machine learning approaches for classifying cell cycle data, indicating the robustness of the features we use in the framework. As such, we suggest the use of MPM-2 analysis and its associated expressive features for integration into HCS approaches.
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The transcriptional coactivator SRC-3 plays a key role in enhancing prostate cancer cell proliferation. Although SRC-3 is highly expressed in advanced prostate cancer, its role in castration-resistant prostate cancer (CRPC) driven...
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The transcriptional coactivator SRC-3 plays a key role in enhancing prostate cancer cell proliferation. Although SRC-3 is highly expressed in advanced prostate cancer, its role in castration-resistant prostate cancer (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human prostate cancer. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both Pten and SRC-3 were inactivated in prostate epithelial cells (Pten3CKO mice), comparing them with mice in which only Pten was inactivated in these cells (PtenCKO mice). SRC-3 deletion impaired cellular proliferation and reduced tumor size. Notably, while castration of PtenCKO control mice increased the aggressiveness of prostate tumors relative to noncastrated counterparts, deletion of SRC-3 in Pten3CKO mice reversed all these changes. In support of this finding, castrated Pten3CKO mice also exhibited decreased levels of phospho-Akt, S6 kinase (RPS6KB1), and phosphorylated S6 protein (RPS6), all of which mediate cell growth and proliferation. Moreover, these tumors appeared to be more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. Lastly, these tumors also displayed lower levels of certain androgen-repressed genes such as cyclin E2 and MMP10. Together, our results show that SRC-3 drives CRPC formation and offer preclinical proof of concept for a transcriptional coactivator as a therapeutic target to abrogate CRPC progression.
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Mammary gland development is dependent upon the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis, this same axis has also been implicated in breast cancer progression. In this study we investigated the effect of a GH ...
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Mammary gland development is dependent upon the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis, this same axis has also been implicated in breast cancer progression. In this study we investigated the effect of a GH antagonist, pegvisomant (Somavert®, Pfizer), on normal mammary gland development and breast cancer xenograft growth. Intraperitoneal administration of pegvisomant resulted in a 60% suppression of hepatic IGF-I mRNA levels and upto a 70–80% reduction of serum IGF-I levels. Pegvisomant administration to virgin female mice caused a significant delay of mammary ductal outgrowth that was associated with a decrease in the number of terminal end buds and reduced branching and complexity of the gland. This effect of pegvisomant was mediated by a complete inhibition of both GH and IGF-IR-mediated signaling within the gland. In breast cancer xenograft studies, pegvisomant caused shrinkage of MCF-7 xenografts, with an initial 30% reduction in tumor volume, which was associated with a 2-fold reduction in proliferation and a 2-fold induction of apoptosis. Long-term growth inhibition of MCF-7 xenografts was noted. In contrast, pegvisomant had no effect on MDA-231 or MDA-435 xenografts, consistent with primary growth of these xenografts being unresponsive to IGF-I both in vitro and in vivo. In MCF-7 xenografts that regressed, pegvisomant had only minor effects upon GHR and IGF-IR signaling. This data supports previous studies indicating a role for GH/IGF in mammary gland development, and suggests that pegvisomant maybe useful for the prevention and/or treatment of estrogen receptor positive breast cancer.
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The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is ...
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The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for anti-angiogenic therapy.
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