22 results on '"Murphy, Maureen E."'
Search Results
2. Elucidating the chain of command: our current understanding of critical target genes for p53-mediated tumor suppression.
- Author
-
Indeglia A and Murphy ME
- Subjects
- Humans, Animals, Genes, Tumor Suppressor, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology
- Abstract
TP53 encodes a transcription factor that is centrally-involved in several pathways, including the control of metabolism, the stress response, DNA repair, cell cycle arrest, senescence, programmed cell death, and others. Since the discovery of TP53 as the most frequently-mutated tumor suppressor gene in cancer over four decades ago, the field has focused on uncovering target genes of this transcription factor that are essential for tumor suppression. This search has been fraught with red herrings, however. Dozens of p53 target genes were discovered that had logical roles in tumor suppression, but subsequent data showed that most were not tumor suppressive, and were dispensable for p53-mediated tumor suppression. In this review, we focus on p53 transcriptional targets in two categories: (1) canonical targets like CDKN1A (p21) and BBC3 (PUMA), which clearly play critical roles in p53-mediated cell cycle arrest/senescence and cell death, but which are not mutated in cancer, and for which knockout mice fail to develop spontaneous tumors; and (2) a smaller category of recently-described p53 target genes that are mutated in human cancer, and which appear to be critical for tumor suppression by p53. Interestingly, many of these genes encode proteins that control broad cellular pathways, like splicing and protein degradation, and several of them encode proteins that feed back to regulate p53. These include ZMAT3, GLS2, PADI4, ZBXW7, RFX7, and BTG2. The findings from these studies provide a more complex, but exciting, potential framework for understanding the role of p53 in tumor suppression.
- Published
- 2024
- Full Text
- View/download PDF
3. An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.
- Author
-
Indeglia A, Leung JC, Miller SA, Leu JI, Dougherty JF, Clarke NL, Kirven NA, Shao C, Ke L, Lovell S, Barnoud T, Lu DY, Lin C, Kannan T, Battaile KP, Yang THL, Batista Oliva I, Claiborne DT, Vogel P, Liu L, Liu Q, Nefedova Y, Cassel J, Auslander N, Kossenkov AV, Karanicolas J, and Murphy ME
- Subjects
- Animals, Humans, Mice, African People genetics, Genes, p53, Neoplasms genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors., Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501., (2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
4. Editorial: Double-edged swords: Important factors connecting metabolic disorders and cancer development - from basic research to translational applications.
- Author
-
Kung CP, Barnoud T, Yao CH, and Murphy ME
- Subjects
- Humans, Metabolic Syndrome, Metabolic Diseases etiology, Neoplasms etiology
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
- Full Text
- View/download PDF
5. PLTP is a p53 target gene with roles in cancer growth suppression and ferroptosis.
- Author
-
Gnanapradeepan K, Indeglia A, Stieg DC, Clarke N, Shao C, Dougherty JF, Murali N, and Murphy ME
- Subjects
- Humans, Apoptosis, Cell Death genetics, Cell Line, Tumor, Tumor Suppressor Protein p53 metabolism, Ferroptosis, Neoplasms genetics, Neoplasms pathology, Phospholipid Transfer Proteins metabolism
- Abstract
The tumor suppressor protein p53 suppresses cancer by regulating processes such as apoptosis, cell cycle arrest, senescence, and ferroptosis, which is an iron-mediated and lipid peroxide-induced cell death pathway. Whereas numerous p53 target genes have been identified, only a few appear to be critical for the suppression of tumor growth. Additionally, while ferroptosis is clearly implicated in tumor suppression by p53, few p53 target genes with roles in ferroptosis have been identified. We have previously studied germline missense p53 variants that are hypomorphic or display reduced activity. These hypomorphic variants are associated with increased risk for cancer, but they retain the majority of p53 transcriptional function; as such, study of the transcriptional targets of these hypomorphs has the potential to reveal the identity of other genes important for p53-mediated tumor suppression. Here, using RNA-seq in lymphoblastoid cell lines, we identify PLTP (phospholipid transfer protein) as a p53 target gene that shows impaired transactivation by three different cancer-associated p53 hypomorphs: P47S (Pro47Ser, rs1800371), Y107H (Tyr107His, rs368771578), and G334R (Gly334Arg, rs78378222). We show that enforced expression of PLTP potently suppresses colony formation in human tumor cell lines. We also demonstrate that PLTP regulates the sensitivity of cells to ferroptosis. Taken together, our findings reveal PLTP to be a p53 target gene that is extremely sensitive to p53 transcriptional function and which has roles in growth suppression and ferroptosis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
6. Shifting the paradigms for tumor suppression: lessons from the p53 field.
- Author
-
Barnoud T, Indeglia A, and Murphy ME
- Subjects
- Animals, Humans, Mutation genetics, Genes, p53 genetics, Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
The TP53 gene continues to hold distinction as the most frequently mutated gene in cancer. Since its discovery in 1979, hundreds of research groups have devoted their efforts toward understanding why this gene is so frequently selected against by tumors, with the hopes of harnessing this information toward the improved therapy of cancer. The result is that this protein has been meticulously analyzed in tumor and normal cells, resulting in over 100,000 publications, with an average of 5000 papers published on p53 every year for the past decade. The journey toward understanding p53 function has been anything but straightforward; in fact, the field is notable for the numerous times that established paradigms not only have been shifted, but in fact have been shattered or reversed. In this review, we will discuss the manuscripts, or series of manuscripts, that have most radically changed our thinking about how this tumor suppressor functions, and we will delve into the emerging challenges for the future in this important area of research. It is hoped that this review will serve as a useful historical reference for those interested in p53, and a useful lesson on the need to be flexible in the face of established paradigms.
- Published
- 2021
- Full Text
- View/download PDF
7. A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.
- Author
-
Powers J, Pinto EM, Barnoud T, Leung JC, Martynyuk T, Kossenkov AV, Philips AH, Desai H, Hausler R, Kelly G, Le AN, Li MM, MacFarland SP, Pyle LC, Zelley K, Nathanson KL, Domchek SM, Slavin TP, Weitzel JN, Stopfer JE, Garber JE, Joseph V, Offit K, Dolinsky JS, Gutierrez S, McGoldrick K, Couch FJ, Levin B, Edelman MC, Levy CF, Spunt SL, Kriwacki RW, Zambetti GP, Ribeiro RC, Murphy ME, and Maxwell KN
- Subjects
- Adult, Age of Onset, Female, Germ-Line Mutation, Humans, Jews, Male, Mutation, Missense, Pedigree, Genetic Predisposition to Disease genetics, Li-Fraumeni Syndrome genetics, Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53 . The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3 , and LCN15 ) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
8. Common genetic variants in the TP53 pathway and their impact on cancer.
- Author
-
Barnoud T, Parris JLD, and Murphy ME
- Subjects
- Animals, Genes, ras, Humans, Retinoblastoma Protein genetics, Retinoblastoma Protein metabolism, Transcription Factors genetics, Transcription Factors metabolism, Neoplasms genetics, Neoplasms metabolism, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-mdm2 genetics, Proto-Oncogene Proteins c-mdm2 metabolism, Signal Transduction genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras, RB, and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases., (© The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)
- Published
- 2019
- Full Text
- View/download PDF
9. Fatty acid transport protein 2 reprograms neutrophils in cancer.
- Author
-
Veglia F, Tyurin VA, Blasi M, De Leo A, Kossenkov AV, Donthireddy L, To TKJ, Schug Z, Basu S, Wang F, Ricciotti E, DiRusso C, Murphy ME, Vonderheide RH, Lieberman PM, Mulligan C, Nam B, Hockstein N, Masters G, Guarino M, Lin C, Nefedova Y, Black P, Kagan VE, and Gabrilovich DI
- Subjects
- Aged, Animals, Arachidonic Acid metabolism, Dinoprostone metabolism, Fatty Acid Transport Proteins antagonists & inhibitors, Female, Humans, Lipid Metabolism, Lipids, Male, Mice, Middle Aged, Neutrophils pathology, STAT5 Transcription Factor metabolism, Fatty Acid Transport Proteins metabolism, Fatty Acids metabolism, Neoplasms metabolism, Neoplasms pathology, Neutrophils metabolism
- Abstract
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E
2 . The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy.- Published
- 2019
- Full Text
- View/download PDF
10. Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α.
- Author
-
Basu S, Gnanapradeepan K, Barnoud T, Kung CP, Tavecchio M, Scott J, Watters A, Chen Q, Kossenkov AV, and Murphy ME
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms mortality, Cell Line, Tumor, Cell Movement, Female, Hepatocyte Nuclear Factor 4 metabolism, Humans, Male, Mice, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms genetics, Neoplasms pathology, Oxidative Phosphorylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha antagonists & inhibitors, Genes, p53, Mutation, Neoplasms metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
- Abstract
Mutant forms of p53 protein often possess protumorigenic functions, conferring increased survival and migration to tumor cells via their "gain-of-function" activity. Whether and how a common polymorphism in TP53 at amino acid 72 (Pro72Arg; referred to here as P72 and R72) impacts this gain of function has not been determined. We show that mutant p53 enhances migration and metastasis of tumors through the ability to bind and regulate PGC-1α and that this regulation is markedly impacted by the codon 72 polymorphism. Tumor cells with the R72 variant of mutant p53 show increased PGC-1α function along with greatly increased mitochondrial function and metastatic capability. Breast cancers containing mutant p53 and the R72 variant show poorer prognosis compared with P72. The combined results reveal PGC-1α as a novel "gain-of-function" partner of mutant p53 and indicate that the codon 72 polymorphism influences the impact of mutant p53 on metabolism and metastasis., (© 2018 Basu et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2018
- Full Text
- View/download PDF
11. Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer.
- Author
-
Veglia F, Tyurin VA, Mohammadyani D, Blasi M, Duperret EK, Donthireddy L, Hashimoto A, Kapralov A, Amoscato A, Angelini R, Patel S, Alicea-Torres K, Weiner D, Murphy ME, Klein-Seetharaman J, Celis E, Kagan VE, and Gabrilovich DI
- Subjects
- Animals, Antigen Presentation immunology, Cell Line, Tumor, Dendritic Cells metabolism, Endosomes immunology, Endosomes metabolism, Female, HSP70 Heat-Shock Proteins immunology, HSP70 Heat-Shock Proteins metabolism, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class I metabolism, Lipid Droplets metabolism, Lysosomes immunology, Lysosomes metabolism, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms metabolism, Neoplasms pathology, Protein Binding, Antigens immunology, Cross-Priming immunology, Dendritic Cells immunology, Lipid Droplets immunology, Lipids immunology, Neoplasms immunology
- Abstract
Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired cross-presentation in DCs is largely associated with defect in trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues.
- Published
- 2017
- Full Text
- View/download PDF
12. Genetic Modifiers of the p53 Pathway.
- Author
-
Basu S and Murphy ME
- Subjects
- Cell Cycle Proteins, Gene Deletion, Gene Frequency, Humans, Nuclear Proteins genetics, Proto-Oncogene Proteins genetics, Genes, Modifier, Genes, p53 physiology, Mutation, Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer; this gene is subject to inactivation by mutation or deletion in >50% of sporadic cancers. Genes that encode proteins that regulate p53 function, such as MDM2, MDM4, and CDKN2A (p14(ARF)) are also frequently altered in tumors, and it is generally believed that the p53 pathway is likely to be inactivated by mutation in close to 100% of human tumors. Unlike most other cancer-relevant signaling pathways, some of the genes in the p53 pathway contain functionally significant single nucleotide polymorphisms (SNPs) that alter the amplitude of signaling by this protein. These variants, thus, have the potential to impact cancer risk, progression, and the efficacy of radiation and chemotherapy. In addition, the p53 pathway plays a role in other biological processes, including metabolism and reproductive fitness, so these variants have the potential to modify other diseases as well. Here we have chosen five polymorphisms in three genes in the p53 pathway for review, two in TP53, two in MDM2, and one in MDM4. These five variants were selected based on the quality and reproducibility of functional data associated with them, as well as the convincingness of epidemiological data in support of their association with disease. We also highlight two other polymorphisms that may affect p53 signaling, but for which functional or association data are still forthcoming (KITLG and ANRIL). Finally, we touch on three questions regarding genetic modifiers of the p53 pathway: Why did these variants arise? Were they under selection pressure? And, is there compelling evidence to support genotyping these variants to better predict disease risk and prognosis?, (Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
13. The HSP70 family and cancer.
- Author
-
Murphy ME
- Subjects
- Animals, Apoptosis, Humans, Mice, Neoplasms drug therapy, Prognosis, Protein Biosynthesis, Protein Folding, Protein Transport, HSP70 Heat-Shock Proteins biosynthesis, HSP70 Heat-Shock Proteins genetics, HSP70 Heat-Shock Proteins metabolism, Neoplasms metabolism, Stress, Physiological physiology
- Abstract
The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascently translating proteins, promote the cellular or organellar transport of proteins, reduce proteotoxic protein aggregates and serve general housekeeping roles in maintaining protein homeostasis. The HSP70 family is the most conserved in evolution, and all eukaryotes contain multiple members. Some members of this family serve specific organellar- or tissue-specific functions; however, in many cases, these members can function redundantly. Overall, the HSP70 family of proteins can be thought of as a potent buffering system for cellular stress, either from extrinsic (physiological, viral and environmental) or intrinsic (replicative or oncogenic) stimuli. As such, this family serves a critical survival function in the cell. Not surprisingly, cancer cells rely heavily on this buffering system for survival. The overwhelming majority of human tumors overexpress HSP70 family members, and expression of these proteins is typically a marker for poor prognosis. With the proof of principle that inhibitors of the HSP90 chaperone have emerged as important anticancer agents, intense focus has now been placed on the potential for HSP70 inhibitors to assume a role as a significant chemotherapeutic avenue. In this review, the history, regulation, mechanism of action and role in cancer of the HSP70 family are reviewed. Additionally, the promise of pharmacologically targeting this protein for cancer therapy is addressed.
- Published
- 2013
- Full Text
- View/download PDF
14. HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells.
- Author
-
Leu JI, Pimkina J, Pandey P, Murphy ME, and George DL
- Subjects
- Animals, Benzoquinones pharmacology, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, HSP70 Heat-Shock Proteins metabolism, Humans, Lactams, Macrocyclic pharmacology, Lysosomes metabolism, Mice, Mice, Nude, Neoplasm Proteins metabolism, Neoplasms metabolism, Proteasome Endopeptidase Complex metabolism, Sulfonamides therapeutic use, Xenograft Model Antitumor Assays, Autophagy drug effects, HSP70 Heat-Shock Proteins antagonists & inhibitors, Neoplasms drug therapy, Sulfonamides pharmacology
- Abstract
The evolutionarily conserved stress-inducible HSP70 molecular chaperone plays a central role in maintaining protein quality control in response to various forms of stress. Constitutively elevated HSP70 expression is a characteristic of many tumor cells and contributes to their survival. We recently identified the small-molecule 2-phenylethyenesulfonamide (PES) as a novel HSP70 inhibitor. Here, we present evidence that PES-mediated inhibition of HSP70 family proteins in tumor cells results in an impairment of the two major protein degradation systems, namely, the autophagy-lysosome system and the proteasome pathway. HSP70 family proteins work closely with the HSP90 molecular chaperone to maintain the stability and activities of their many client proteins, and PES causes a disruption in the HSP70/HSP90 chaperone system. As a consequence, many cellular proteins, including known HSP70/HSP90 substrates, accumulate in detergent-insoluble cell fractions, indicative of aggregation and functional inactivation. Overall, PES simultaneously disrupts several cancer critical survival pathways, supporting the idea of targeting HSP70 as a potential approach for cancer therapeutics., (©2011 AACR.)
- Published
- 2011
- Full Text
- View/download PDF
15. Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model.
- Author
-
Azzam GA, Frank AK, Hollstein M, and Murphy ME
- Subjects
- Animals, Gene Knock-In Techniques methods, Genome-Wide Association Study, Humans, Mice, Mice, Mutant Strains, Neoplasms epidemiology, Polymorphism, Genetic genetics, Risk Factors, Tissue Distribution genetics, Tumor Suppressor Protein p53 metabolism, Apoptosis genetics, Codon genetics, Disease Models, Animal, Neoplasms genetics, Neoplasms pathology, Tumor Suppressor Protein p53 genetics
- Abstract
Currently there are several dozen human polymorphisms that have been loosely associated with cancer risk. Correlating such variants with cancer risk has been challenging, primarily due to factors such as genetic heterogeneity, contributions of diet and environmental factors, and the difficulty in obtaining large sample sizes for analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. Recently, several groups have modeled human cancer susceptibility polymorphisms in the mouse. Remarkably, in each case these mouse models have accurately reflected human phenotypes, and clarified the contribution of these variants to cancer risk. We recently reported on a mouse model for the codon 72 polymorphism in p53, and found that this polymorphism regulates the ability to cooperate with NF-kB and induce apoptosis. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner; such tissue-specific effects of polymorphic variants represent an added challenge to human cancer risk association studies. The data presented here support the premise that modeling human polymorphisms in the mouse represents a powerful tool to assess the impact of these variants on cancer risk, progression and therapy.
- Published
- 2011
- Full Text
- View/download PDF
16. ARF, autophagy and tumor suppression.
- Author
-
Pimkina J and Murphy ME
- Subjects
- ADP-Ribosylation Factor 1 metabolism, Animals, Antineoplastic Agents pharmacology, Autophagy genetics, Chloroquine pharmacology, Gene Silencing, Genes, p53, Humans, Mice, Models, Biological, Neoplasm Transplantation, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins metabolism, ADP-Ribosylation Factor 1 physiology, Neoplasms metabolism
- Abstract
Autophagy plays a critical role in the initiation and progression of tumors. The exact nature of this role, however, is complex. Autophagy is suppressive to tumor initiation, and reduces genomic instability. Genes with key roles in autophagy are mutated in human cancer, and knockout mice for certain autophagy genes are predisposed to cancer. Conversely, established tumors appear to utilize autophagy in order to survive periods of metabolic or hypoxic stress. Consistent with this, small molecule inhibitors of autophagy like chloroquine are effective anticancer agents for certain tumor types. The consensus appears to be that autophagy suppresses tumor initiation, but promotes the survival of established tumors. But this premise may be over-simplified. Several groups have recently shown that the ARF tumor suppressor can induce autophagy. While some groups have found that ARF-mediated autophagy is cytotoxic to tumor cells, we have shown that ARF's autophagy function may promote the survival and progression of certain tumors. We have previously shown that silencing ARF limits autophagy and the development of p53-null lymphomas. In this addendum, we show this is not true for primary p53-null sarcoma cells. Rather, ARF-silencing enhances sarcoma development. These data suggest that the survival-benefit of ARF, and possibly also of autophagy, may be restricted to certain tumor types.
- Published
- 2009
- Full Text
- View/download PDF
17. A novel cancer therapy approach targeting microtubule function.
- Author
-
Murphy ME and Cassimeris L
- Subjects
- Gene Expression Regulation, Neoplastic, Humans, Microtubules physiology, Neoplasms therapy, RNA, Small Interfering genetics, Stathmin genetics
- Published
- 2006
- Full Text
- View/download PDF
18. Regulation of cell death in oncogenesis.
- Author
-
Murphy ME
- Subjects
- Animals, Humans, Apoptosis physiology, Cell Transformation, Neoplastic pathology, Neoplasms pathology
- Published
- 2005
- Full Text
- View/download PDF
19. p53 moves to mitochondria: a turn on the path to apoptosis.
- Author
-
Murphy ME, Leu JI, and George DL
- Subjects
- Cytochromes c metabolism, Humans, Mitochondria genetics, Neoplasms genetics, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Transport physiology, Stress, Physiological genetics, Tumor Suppressor Protein p53 genetics, bcl-2 Homologous Antagonist-Killer Protein metabolism, Apoptosis physiology, Mitochondria metabolism, Neoplasms metabolism, Stress, Physiological metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
It has been said that no matter which direction cancer research turns, the p53 tumor suppressor protein comes into view. The widespread role of p53 as a suppressor of tumor development is believed to rely on its ability to induce programmed cell death in response to stress, either the replicative stress associated with uncontrolled cellular proliferation, or the environmental stresses that accompany tumor development, such as hypoxia. For some time it has been believed that the role of p53 in inducing apoptosis in response to such stress was as a master regulator coordinating the expression of other molecules whose ultimate role was the execution of the cell. New data, however, suggest that p53 itself also has a direct role in accomplishing cell death, at the mitochondria.
- Published
- 2004
20. The thousand doors that lead to death: p53-dependent repression and apoptosis.
- Author
-
Murphy ME
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Clusterin, Complement Inactivator Proteins metabolism, Cytoplasm, DNA Damage drug effects, Gamma Rays, Glycoproteins antagonists & inhibitors, Glycoproteins genetics, Humans, Molecular Chaperones antagonists & inhibitors, Molecular Chaperones genetics, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasms genetics, Neoplasms metabolism, Promoter Regions, Genetic, RNA, Messenger drug effects, RNA, Messenger genetics, RNA, Messenger radiation effects, Transcription, Genetic drug effects, Transcription, Genetic radiation effects, Apoptosis radiation effects, DNA Damage radiation effects, Glycoproteins metabolism, Molecular Chaperones metabolism, Neoplasms pathology, Tumor Suppressor Protein p53 physiology
- Published
- 2003
- Full Text
- View/download PDF
21. Fatty acid transporter 2 reprograms neutrophils in cancer
- Author
-
Veglia, Filippo, Tyurin, Vladimir A., Blasi, Maria, De Leo, Alessandra, Kossenkov, Andrew, Donthireddy, Laxminarasimha, Jerrick, To Tsun Ki, Schug, Zach, Basu, Subhasree, Wang, Fang, Ricciotti, Emanuela, DiRusso, Concetta, Murphy, Maureen E., Vonderheide, Robert H., Lieberman, Paul M., Mulligan, Charles, Nam, Brian, Hockstein, Neil, Masters, Gregory, Guarino, Michael, Lin, Cindy, Nefedova, Yulia, Black, Paul, Kagan, Valerian E., and Gabrilovich, Dmitry
- Subjects
Neutrophils ,Neoplasms ,Fatty Acids ,Humans ,Fatty Acid Transport Proteins ,Article - Abstract
Summary Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that are critically important for the regulation of immune responses in cancer. They contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limits selective targeting of these cells. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSC. The main mechanism of FATP2 mediated suppressive activity involved uptake of arachidonic acid (AA) and synthesis of prostaglandin E2 (PGE2). The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to selectively inhibit the functions of PMN-MDSC and improve the effect of cancer therapy.
- Published
- 2019
22. Heat Shock Protein-70 Inhibition by the Small-Molecule 2-phenylethynesulfonamide Impairs Protein Clearance Pathways in Tumor Cells
- Author
-
Leu, J. I-Ju, Pimkina, Julia, Pandey, Pooja, Murphy, Maureen E., and George, Donna L.
- Subjects
Proteasome Endopeptidase Complex ,Sulfonamides ,Lactams, Macrocyclic ,Mice, Nude ,Xenograft Model Antitumor Assays ,Article ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Mice ,Cell Line, Tumor ,Neoplasms ,Autophagy ,Benzoquinones ,Animals ,Humans ,Female ,HSP70 Heat-Shock Proteins ,Lysosomes - Abstract
The evolutionarily conserved stress-inducible HSP70 molecular chaperone plays a central role in maintaining protein quality control in response to various forms of stress. Constitutively elevated HSP70 expression is a characteristic of many tumor cells and contributes to their survival. We recently identified the small-molecule 2-phenylethyenesulfonamide (PES) as a novel HSP70 inhibitor. Here we present evidence that PES-mediated inhibition of HSP70-family proteins in tumor cells results in an impairment of the two major protein degradation systems, namely the autophagy-lysosome system as well as the proteasome pathway. HSP70-family proteins work closely with the HSP90 molecular chaperone to maintain the stability and activities of their many client proteins and PES causes a disruption in the HSP70/HSP90 chaperone system. As a consequence, many cellular proteins, including known HSP70/HSP90 substrates, accumulate in detergent-insoluble cell fractions, indicative of aggregation and functional inactivation. Overall, PES simultaneously disrupts several cancer-critical survival pathways, supporting the idea of targeting HSP70 as a potential approach for cancer therapeutics.
- Published
- 2011
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.