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Abstract A cDNA probe has been used to investigate the molecular genetics of antithrombin III deficiency in 15 kindreds with hereditary thrombosis. The results show that the origins of this disorder are heterogeneous. Complete deletion of... more
Abstract A cDNA probe has been used to investigate the molecular genetics of antithrombin III deficiency in 15 kindreds with hereditary thrombosis. The results show that the origins of this disorder are heterogeneous. Complete deletion of one ATIII allele has occurred in two different families. Affected individuals in the remaining 13 families have two copies of the ATIII gene, and both alleles appear grossly normal at the resolution of Southern blotting. Hereditary thrombosis in 12 of these families is caused by (1) dysfunctional mutations which map in the ATIII locus or (2) lesions at unlinked loci which effect antithrombin modification and maturation. The presence of a dysfunctional ATIII gene encoding an inactive, electrophoretically abnormal anticoagulant molecule has been demonstrated for the final kindred, and this dysfunctional gene has been isolated by molecular cloning.
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Background and Aims Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death that develops as a consequence of obesity, cirrhosis, and chronic hepatitis. However, the pathways along which these changes occur remain... more
Background and Aims Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death that develops as a consequence of obesity, cirrhosis, and chronic hepatitis. However, the pathways along which these changes occur remain incompletely understood. Approach and Results In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high‐fat diets. IKKβ phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKβ also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter’s deubiquitination. In HCCs arising in DEN/CCl4‐treated mice, USP30 deletion attenuated lipogenesis, inflammation, and tumorigenesis regardless of diet. The combination of ACLY inhibitor and programmed death ligand 1 antibody largely suppressed chemical‐induced hepatocarcinogenesis. The IKKβ‐USP30‐ACLY axis was also found to be up‐regulated in huma...
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Antithrombin-III-Hamilton is a structural mutant of antithrombin III with defective serine protease reactivity, demonstrable in three members of a French Canadian family. The propositus, a 54-year-old man with a history of recurrent... more
Antithrombin-III-Hamilton is a structural mutant of antithrombin III with defective serine protease reactivity, demonstrable in three members of a French Canadian family. The propositus, a 54-year-old man with a history of recurrent thromboembolic events, and his two asymptomatic grown children are heterozygous for the mutant antithrombin III gene. In all three individuals, the immunoreactive antithrombin III level is normal, while the antithrombin and antifactor Xa activity is approximately 50% of the control value. Two dimensional immunoelectrophoresis of antithrombin-III-Hamilton in the presence of heparin is normal. Purified antithrombin-III-Hamilton did not form thrombin-antithrombin III complex when incubated with thrombin for up to 30 minutes. The normal and mutant antithrombin III alleles of the propositus could be distinguished by linkage to Pstl restriction fragment length polymorphisms (RFLP). Genomic DNA from the propositus was cloned into EMBL 3 phage vectors and two cl...
Research Interests: Chemistry, Molecular Biology, Biology, Medicine, Thrombin, and 15 moreHeparin, Mutation, Blood, Pedigree, Clinical Sciences, Codon, Amino Acid Sequence, Base Sequence, Protein Binding, Antithrombin, Molecular Sequence Data, alleles, binding sites, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
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The transcription factor c-Myc (hereafter Myc) is among the most frequently deregulated oncoproteins. Inhibition of Myc triggers proliferative arrest of transformed cells and promotes tumor regression and/or apoptosis. Myc is also... more
The transcription factor c-Myc (hereafter Myc) is among the most frequently deregulated oncoproteins. Inhibition of Myc triggers proliferative arrest of transformed cells and promotes tumor regression and/or apoptosis. Myc is also developmentally necessary and myc-/- embryos die at E9.5-10.5. However, Myc's role in the maintenance of specific tissues has been shown to be of variable importance and necessity. For example, several studies of Myc's role in promoting liver regeneration following partial hepatectomy (PH) have given conflicting results, although all show Myc to be generally dispensable for this function. We have used a conditional murine knockout (KO) model of Myc to study its role in liver regeneration. By employing a mycfl/fl;Alb-Cre+ model in which loss of Myc occurs perinatally, we studied non-oncogenic liver proliferation and metabolism in the absence of Myc signaling. We employed basic metabolic benchmarks of liver function including measurements of triglyce...
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Research Interests: Biology, Cell Biology, Apoptosis, Medicine, Cell line, and 15 moreHumans, Reactive Oxygen Species, Mitochondrial Dynamics, Animals, MITOCHONDRIAL BIOGENESIS, Phenotype, Rats, Oxidative phosphorylation, Cell Proliferation, Ribonucleotides, Cell Survival, Adenosine Triphosphate, Mitochondrion, Mitochondrial Fission, and MFN
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Background: c-Myc (Myc) is a global transcription factor that controls the expression of a large part of the human genome. The numerous Myc target genes function in a variety of normal cellular processes whose collective expression of... more
Background: c-Myc (Myc) is a global transcription factor that controls the expression of a large part of the human genome. The numerous Myc target genes function in a variety of normal cellular processes whose collective expression of these processes is referred to as the “Myc phenotype”. One such cellular process is the regulation of mitochondrial biogenesis. Objectives: To understand the specific influence that Myc has on mitochondrial structure and function. We hypothesize that Myc is involved in the regulation of both the production and destruction of mitochondria, and that the ability of Myc to maintain this balance has an impact on cellular transformation. Design/Method: Various cell lines that allow for the manipulation of Myc levels have been used. These include cells that have been engineered to have inducible Myc over-expression as well as inducible expression of Myc shRNA. These strains were used in a series of assays that measured different aspects of the Myc effect on m...
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Background & AimsThe c-Myc (Myc) bHLH-ZIP transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation and proliferation. This “Myc... more
Background & AimsThe c-Myc (Myc) bHLH-ZIP transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation and proliferation. This “Myc Network” cross-talks with the “Mlx Network”, which consists of the Myc-like proteins MondoA and ChREBP and Max-like Mlx. Together, this “Extended Myc Network” regulates both common and distinct genes targets. Here we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism and spontaneous tumorigenesis.MethodsWe examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc+Mlx (double KO or DKO) to repopulate the liver over an extended period of time in a murine model of Type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes and transcriptomes of the livers to those from previously characterized MycKO, ChrebpKO and MycKO x ChrebpKO mice.ResultsHep...
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F-MEL cells were transfected with the c-jun antisense gene located downstream of a glucocorticoid-inducible MMTV promoter, and the obtained cells were named c-jun AS cells. When the c-jun AS cells were treated with dexamethasone (DEX) in... more
F-MEL cells were transfected with the c-jun antisense gene located downstream of a glucocorticoid-inducible MMTV promoter, and the obtained cells were named c-jun AS cells. When the c-jun AS cells were treated with dexamethasone (DEX) in DMEM supplemented with 10% serum, the growth of the cells was completely suppressed for a duration of 16 days with a high cell viability exceeding 86%. The c-jun expression in the c-jun AS cells was suppressed moderately in the absence of DEX and strongly in the presence of DEX. The c-jun AS cells grew well and reached a density of 10(6) cells/mL without supplementation of any serum components. Viability was greater than 80% after the cells had been cultured for 8 days in the absence of DEX. The c-jun AS cells stayed at a constant cell density and high viability above 80% for 8 days when they were cultured in the presence of DEX under serum deprivation. In contrast, the wild type F-MEL cells were unable to grow and died by apoptosis in 3 days under serum deprivation. Internucleosomal cleavage of DNA, a landmark of apoptosis, was clearly detectable. Thus the c-jun AS cell line that is resistant to apoptosis induced by serum deprivation and can reversibly and viably be growth-arrested was established. A dual-signal model was proposed to explain the experimental result, the interlinked regulation of apoptosis, and growth by c-jun.
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One of the most common chromosomal abnormalities in prostate cancer involves loss of 10q22-qter. Rarely, a smaller deletion, involving 10q24-q25, has been observed, suggesting the presence of a tumor suppressor gene at this site. We... more
One of the most common chromosomal abnormalities in prostate cancer involves loss of 10q22-qter. Rarely, a smaller deletion, involving 10q24-q25, has been observed, suggesting the presence of a tumor suppressor gene at this site. We previously demonstrated that the MXI1 gene maps to 10q24-q25 and is mutated in some tumors with cytogenetically detectable deletions of this locus. MXI1 encodes a basic-helix-loop-helix protein that suppresses the transcriptional activity of the MYC oncoprotein by competing for the common dimerization partner, MAX, and binding to identical DNA sites. Because more than 90% of prostate tumors contain no cytogenetic abnormality of 10q, the relevance of MXI1 loss and/or mutation to the vast majority of cases remains unclear. We prospectively evaluated prostate tumors for loss of MXI1 by fluorescence in situ hybridization (FISH) and cytogenetic techniques. Twenty-one of 40 tumors (53%) demonstrated loss of a single MXI1 allele as determined by FISH. Ten cases with cytogenetically normal 10qs, but with FISH-documented deletion of MXI1, were examined at the molecular level, and eight mutations were identified, albeit at low frequency. Five of the mutant proteins were unable to bind DNA in association with MAX. We conclude that MXI1 gene loss in prostate cancer is common and most frequently involves a cytogenetically undetectable deletion.
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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the underlying pathophysiology of HCC is highly complex. In this study, we report that, in a bioinformatic screen of 2,783 genes encoding metabolic... more
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the underlying pathophysiology of HCC is highly complex. In this study, we report that, in a bioinformatic screen of 2,783 genes encoding metabolic enzymes, GNPAT, which encodes the enzyme glyceronephosphate O-acyltransferase, is amplified, upregulated, and highly correlated with poor clinical outcome in human patients with HCC. High GNPAT expression in HCC was due to its amplification and transcriptional activation by the c-Myc/KDM1A complex. GNPAT compensated the oncogenic phenotypes in c-Myc–depleted HCC cells. Mechanistically, GNPAT recruited the enzyme USP30, which deubiquitylated and stabilized dynamin-related protein 1 (DRP1), thereby facilitating regulation of mitochondrial morphology, lipid metabolism, and hepatocarcinogenesis. Inhibition of GNPAT and DRP1 dramatically attenuated lipid metabolism and hepatocarcinogenesis. Furthermore, DRP1 mediated the oncogenic phenotypes driven by GNP...
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The pediatric liver cancer hepatoblastoma (HB) often expresses mutant forms of β-catenin and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing these β-catenin mutants and the constitutively... more
The pediatric liver cancer hepatoblastoma (HB) often expresses mutant forms of β-catenin and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing these β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other human cancers also express mutant forms of NFE2L2/NRF2 (NFE2L2), a bHLH transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis in a context-and time-dependent manner. We show here that two patient-derived NFE2L2 missense mutants, L30P and R34P, markedly accelerate HB growth in association with widespread cyst formation, an otherwise uncommon feature of human HB. Surprisingly, we found that any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus providing direct evidence for NFE2L2’s role as an oncoprotein. Each tumor group displayed distinct features but shared a similarly deregulated set of ...
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Clonal lines of Friend murine erythroleukemia (F-MEL) cells have been generated following transfection with c-myc or c-myb expression plasmids. These clones produce high levels of abnormally regulated proto-oncogene transcripts and fail... more
Clonal lines of Friend murine erythroleukemia (F-MEL) cells have been generated following transfection with c-myc or c-myb expression plasmids. These clones produce high levels of abnormally regulated proto-oncogene transcripts and fail to terminally differentiate in the presence of dimethyl sulfoxide. To determine the relative levels at which the two proto-oncogenes might exert their inhibitory effects, we asked whether these clones could express differentiated functions in the absence of terminal differentiation. It was found that exposure of c-myc-transfected cells to hemin allows for the induction of hemoglobin, whereas c-myb-transfected cells were refractory to hemin induction. It thus appears that c-myb exerts a more globally suppressive effect on F-MEL-differentiated functions than does c-myc and may prevent the expression of those events that can otherwise be dissociated from the terminally differentiated state.
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Purpose This study investigated alpha 4 beta 1/ Very Late Antigen-4 (α4β1/ VLA-4)-integrin targeted nanotherapy approach to deliver a new lipase-labile prodrug. Experimental Design A phospholipid-based MYC-MAX inhibitor prodrug (MI1-PD)... more
Purpose This study investigated alpha 4 beta 1/ Very Late Antigen-4 (α4β1/ VLA-4)-integrin targeted nanotherapy approach to deliver a new lipase-labile prodrug. Experimental Design A phospholipid-based MYC-MAX inhibitor prodrug (MI1-PD) was synthesized, and its inherent anti-proliferate potency was compared to the lipid-free compound (MI1) using mouse multiple myeloma (MM) cell line (5TGM1). VLA-4-targeted perfluorocarbon (PFC) nanoparticles binding to 5TGM1 cells was measured and compared to biomarker expression assessed with flow cytometry using antibodies. The efficacy of MI1-PD incorporated into non-targeted and VLA-4-targeted PFC NP exposed to 5TGM1 cells was assessed with MTT assays, Annexin V and cell cycle analysis. Results MI1-PD was more potent by several orders of magnitude than its free drug counterpart in culture. Targeted NP binding correlated well with biomarker expression assessment by flow cytometry in 5TGM1 cells. Non-targeted NPs had no appreciable binding to 5TGM...
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Deubiquitinases (DUBs) play essential roles in normal cell proliferation and tumor growth. However, the molecular mechanisms of DUBs on hepatocellular carcinoma (HCC) remains largely unknown. In this study, based on analysis of several... more
Deubiquitinases (DUBs) play essential roles in normal cell proliferation and tumor growth. However, the molecular mechanisms of DUBs on hepatocellular carcinoma (HCC) remains largely unknown. In this study, based on analysis of several HCC datasets, we found that the USP21 gene, which encodes a member of the ubiquitin-specific protease family, is highly amplified and overexpressed in HCCs, with the extent of this up-regulation significantly correlating with poor clinical outcomes. Inhibition of USP21 in HCC cell lines decreased cell proliferation, anchorage-independent growth, cell cycle progression, and in vivo tumor growth. Conversely, ectopic expression of USP21 transformed the normal human hepatocyte line HL-7702 and increased the tumorigenicity of the HCC cell line MHCC97L. Mechanistically, USP21 stabilized MEK2 by decreasing its polyubiquitination at Lys48, thereby activating the ERK signaling pathway. Importantly, MEK2 partially mediated the optimal expression of USP21-mediat...
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Virtually all tumors undergo some form of metabolic re-programming to match anabolic needs with energy supply. The best-known form of this is the Warburg effect by which tumors become more reliant on glycolysis over mitochondrial... more
Virtually all tumors undergo some form of metabolic re-programming to match anabolic needs with energy supply. The best-known form of this is the Warburg effect by which tumors become more reliant on glycolysis over mitochondrial oxidative phosphorylation, even when their oxygen supply is abundant. Nonetheless, mitochondria retain some residual activity in order to provide both ATP and critical metabolic building blocks and other substrates for processes such as lipid biosynthesis and protein acetylation. The pyruvate dehydrogenase (PDH) complex (PDC) is the main enzymatic link between glycolysis and the TCA cycle and irreversibly converts the end-stage glycolytic product pyruvate into the critical TCA substrate, acetyl-coenzyme A (AcCoA). In a mouse model of the pediatric liver cancer hepatoblastoma (HB), we recently showed PDH to be highly up-regulated, despite reduced mitochondrial function. We postulated that this might represent a response to pyruvate depletion due to upstream ...
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Immediate early genes involved in controlling cell proliferation are rapidly and transiently induced following stimulation of susceptible cells with serum. To study how oncoproteins regulate immediate early genes, we examined serum... more
Immediate early genes involved in controlling cell proliferation are rapidly and transiently induced following stimulation of susceptible cells with serum. To study how oncoproteins regulate immediate early genes, we examined serum inducibility of these genes in cells transformed by various oncoproteins. We found that induction of the immediate early gene, c-fos, by serum stimulation was markedly attenuated in four independent cell lines stably transformed by the v-Src tyrosine kinase. Cells chronically transformed by other oncoproteins implicated in tyrosine kinase signaling pathways, including v-Sis, v-Ras, and v-Raf, showed the same pattern of attenuation. In contrast, serum inducibility of c-fos was not attenuated in cells transformed by simian virus 40, which is thought to transform cells through a different pathway. Cell cycle analyses showed that proliferation of these transformed cell lines could be arrested effectively in 0.1% serum, demonstrating that the attenuation was n...
Research Interests: Molecular Biology, Biology, Cell Cycle, Transcription Factors, Medicine, and 12 moreGene expression, Signal Transduction, Biological Sciences, Molecular and cellular biology, Animals, Rats, Culture Media, DNA binding proteins, Tyrosine Kinase, Protein tyrosine kinases, Medical and Health Sciences, and In Vitro Techniques
The proteins encoded by cellular and viral src genes are believed to be involved in the transmission of mitogenic signals, the nuclear recipients of which are largely unknown. In this work, we report that four different v-src-transformed... more
The proteins encoded by cellular and viral src genes are believed to be involved in the transmission of mitogenic signals, the nuclear recipients of which are largely unknown. In this work, we report that four different v-src-transformed cell lines from three different species possess elevated levels of junB transcripts. Transient expression of junB promoter-chloramphenicol acetyltransferase constructs in NIH 3T3 cells was used to demonstrate that the increase in junB transcripts was specifically associated with v-src expression and could not be recapitulated with a c-src, v-H-ras, or v-raf expression vector. Deletion mutants were used to localize the v-src-responsive region in the junB promoter to a 121-nucleotide region encompassing the CCAAT and TATAA elements. This region is distinct from one in the 5' untranslated region of the junB gene which is required to maintain its high-level basal expression. Point mutagenesis of the junB TATAA box completely abolished v-src responsi...
Research Interests: Cellular Biology, Molecular Biology, Biology, Medicine, Biological Sciences, and 15 moreDNA, Molecular and cellular biology, Mice, Animals, T cells, Plasmids, Transfection, Amino Acid Sequence, Base Sequence, Gene Expression Regulation, Adenosine Triphosphate, Molecular Sequence Data, Restriction Mapping, Protein tyrosine kinases, and Medical and Health Sciences
Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a... more
Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC “knockout” (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas was only modestly slowed in the face of 80%–90% reductions in AcCoA and significant alterations in the levels of key tricarboxylic acid (TCA) cycle intermediates and amino acids. Overall, oxphos activity in KO livers ...
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Friend murine erythroleukemia (F-MEL) cells were transfected with a plasmid bearing tandemly arranged mouse c-myc antisense and dihydrofolate reductase transcription units. Sixteen clones were isolated, each containing unrearranged c-myc... more
Friend murine erythroleukemia (F-MEL) cells were transfected with a plasmid bearing tandemly arranged mouse c-myc antisense and dihydrofolate reductase transcription units. Sixteen clones were isolated, each containing unrearranged c-myc sequences and expressing high levels of antisense transcripts. All antisense clones examined contained reduced amounts of cytoplasmic endogenous c-myc transcripts. The kinetics of reaccumulation of endogenous c-myc mRNA during a 24-h exposure to dimethyl sulfoxide (DMSO) were also retarded and the ultimate transcript levels attained were less than in control cells. Antisense clones grew as well as control F-MEL cells in medium containing 10% fetal calf serum but at only a half and a quarter of the control rates in media containing 5 and 2% serum, respectively. Antisense clones differentiated faster and to a greater degree than control cells following DMSO exposure. myc antisense transcript expression was increased by growing cells in methotrexate, w...
Research Interests: Molecular Biology, RNA, Biology, DNA replication, Medicine, and 14 moreCell Culture, Cell Division, Biological Sciences, Cell line, Cell Differentiation, Molecular and cellular biology, Mice, Animals, Plasmids, Transfection, Antisense RNA, Interphase, Proto-Oncogenes, and Medical and Health Sciences
The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC-MAX dimerization is limited by poor efficacy. We determined the efficacy of lipase labile MYC-MAX inhibitor prodrug... more
The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC-MAX dimerization is limited by poor efficacy. We determined the efficacy of lipase labile MYC-MAX inhibitor prodrug (MI1-PD) loaded nanoparticles targeted via integrin {alpha 4 beta1 α4β1) or Very Late Antigen-1 (VLA-4)} in myeloma mice. We hypothesized that NPs containing specific targeting to myeloma cells, would enhance the therapeutic efficacy of MI1-PD containing NPs. The antiproliferative activity of intergin VLA-4-Targeted MI-1PD NPs (iTM-NPs) was determined in mouse cell line (5TGM1) in vitro and its effect on the survival in C57Bl/KaLwRij-5TGM1 murine model of myeloma in vivo. iTM-NPs (approximately 20 nm in diameter, 5% w/w MI1-PD loading) under in vitro conditions exhibited inhibition of cell growth compared to the controls. Also, C57Bl/KaLwRij-5TGM1 mice that received intravenous injection of iTM-NPs demonstrated greater survival rate over the controls. Thes...
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Background: Tumor growth beyond a few millimeters in size requires the development of a neovasculature. In addition to providing a portal for the systemic dissemination of metastatic cells, this allows the tumor bed to overcome the severe... more
Background: Tumor growth beyond a few millimeters in size requires the development of a neovasculature. In addition to providing a portal for the systemic dissemination of metastatic cells, this allows the tumor bed to overcome the severe hypoxia, acidosis, and nutrient deprivation that otherwise limits tumor growth. Early research presumed the development of genetically and functionally normal tumor vasculature from normal host tissue. Anti-angiogenic agents were thus developed to inhibit tumor blood supply with the hope that the presumed normal tumor vascular endothelial cells (EC's), would be less inclined to develop drug resistance. Thus far, however, the experience with these agents has been one of only incremental improvement in patient survival. We have previously demonstrated that tumor cells can differentiate, in vivo, into an EC phenotype and form functional tumor vasculature. Formation of these “tumor derived endothelial cells” (TDEC's) offers a partial explanatio...
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c-Myc is a bHLH-ZIP transcription factor that is deregulated in a variety of human cancers. More specifically, c-Myc heterodimerizes with another bHLH-ZIP partner protein, Max, to bind to specific sequences (E-Boxes: CAC/TGTG) located... more
c-Myc is a bHLH-ZIP transcription factor that is deregulated in a variety of human cancers. More specifically, c-Myc heterodimerizes with another bHLH-ZIP partner protein, Max, to bind to specific sequences (E-Boxes: CAC/TGTG) located near the transcriptional start sites of its numerous target genes. Because c-Myc's highly variable downstream effects are difficult to attack individually, directly inhibiting the association between c-Myc and Max association by interfering with their bHLH-ZIP-mediated heterodimerization has emerged as an attractive therapeutic strategy. Thus far, high throughput screens of chemical libraries have identified a number of small molecules that specifically inhibit the c-Myc-Max association. However, these synthetic compounds and their analogs are generally of low potency and therefore have limited clinical utility. Here we report identification of celastrol, a naturally occurring triterpenoid, as a potent c-Myc inhibitor. We sought to further assess c...
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Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC... more
Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC progression, regression and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain Complexes I and II to respiration. The uncoupling of Complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA-Seq studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity and further metabolic re-progra...
Research Interests: Biology, Biological Chemistry, Cancer Research, DNA repair, Medicine, and 15 moreGene Silencing, Transgenic Mice, Biological Sciences, Humans, Liver, Reactive Oxygen Species, Female, Animals, Male, Hepatocellular Carcinoma, CHEMICAL SCIENCES, Carcinogenesis, Gene expression profiling, Liver neoplasms, and Medical and Health Sciences
Hepatoblastoma (HB), the most common childhood liver cancer, is associated with seven distinct histologic subtypes and variable degrees of clinical aggressiveness and presentation. Yet it is among the least genomically altered tumors... more
Hepatoblastoma (HB), the most common childhood liver cancer, is associated with seven distinct histologic subtypes and variable degrees of clinical aggressiveness and presentation. Yet it is among the least genomically altered tumors known, with about half of HBs showing mutation and/or dysregulation of the Wnt/β-catenin and Hippo pathways. This raises the question of how this mutational simplicity can generate such biological and histologic complexity. Recent work shows that the identity of the underlying β-catenin mutation is a major contributor. Mutation or over-expression of the NFE2L2/NRF2 transcription factor, previously thought only to promote anti-oxidant responses, has also recently been shown to accelerate the growth of HBs generated by mutations in the Wnt/β-catenin and Hippo pathways while imparting novel features such as the tumor-associated cysts and necrosis. Moreover, patient-associated NFE2L2 mutations are overtly transforming when co-expressed with either mutant β-...
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Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and... more
Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1-4, Mnt and Mga) each of which heterodimerizes with Max and largely oppose Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted sets of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members with particular emphasis on the roles played by Max, Mlx and Mxd proteins in suppressing normal and neoplastic growth. These roles are complex due to the temporally- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.
Supplementary Information. Contains Figure S1-S5, Table S1-S2, and their respective legends. (DOCX 1621Â kb)