Author
William A. Freed-Pastor
Other affiliations: Columbia University, Harvard University
Bio: William A. Freed-Pastor is an academic researcher from Massachusetts Institute of Technology. The author has contributed to research in topics: Medicine & Pancreatic cancer. The author has an hindex of 11, co-authored 19 publications receiving 2004 citations. Previous affiliations of William A. Freed-Pastor include Columbia University & Harvard University.
Topics: Medicine, Pancreatic cancer, Biology, Mutant, Transcription factor
Papers
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TL;DR: Mechanisms by which Mutant p53 exerts its cellular effects are reviewed, with a particular focus on the burgeoning mutant p53 transcriptome, and the biological and clinical consequences of mutant p 53 gain of function are discussed.
Abstract: There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.
1,033 citations
TL;DR: It is found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology, which implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53.
735 citations
TL;DR: It is demonstrated that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and the mechanism by which this occurs is outlined.
240 citations
TL;DR: It is surmised that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex, which means that not only might mutants p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI-SNF tumor suppressor function in mutant p 53 tumors may also have therapeutic potential.
Abstract: Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.
119 citations
TL;DR: The results provide several unanticipated and interconnected findings that enable stable formation of p53-DNA complexes to divergent binding sites via DNA-induced conformational changes within the DBD itself.
95 citations
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TL;DR: This Perspective has organized known cancer-associated metabolic changes into six hallmarks: deregulated uptake of glucose and amino acids, use of opportunistic modes of nutrient acquisition, useof glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, increased demand for nitrogen, alterations in metabolite-driven gene regulation, and metabolic interactions with the microenvironment.
3,565 citations
TL;DR: Some of the emerging molecular mechanisms through which mutant p53 proteins can exert oncogenic functions, including invasion, metastasis, proliferation and cell survival, are highlighted.
Abstract: In the past fifteen years, it has become apparent that tumour-associated p53 mutations can provoke activities that are different to those resulting from simply loss of wild-type tumour-suppressing p53 function. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Here we highlight some of the emerging molecular mechanisms through which mutant p53 proteins can exert these oncogenic functions.
1,463 citations
TL;DR: There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression.
1,235 citations
TL;DR: TP53 is the most frequently mutated gene in human cancer and must be interpreted to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might it restore its tumor-suppressive activities in cancer.
1,215 citations
TL;DR: This review will examine some of the alterations in lipid metabolism that have been reported in cancer, at both cellular and organismal levels, and discuss how they contribute to different aspects of tumourigenesis.
Abstract: Lipids form a diverse group of water-insoluble molecules that include triacylglycerides, phosphoglycerides, sterols and sphingolipids. They play several important roles at cellular and organismal levels. Fatty acids are the major building blocks for the synthesis of triacylglycerides, which are mainly used for energy storage. Phosphoglycerides, together with sterols and sphingolipids, represent the major structural components of biological membranes. Lipids can also have important roles in signalling, functioning as second messengers and as hormones. There is increasing evidence that cancer cells show specific alterations in different aspects of lipid metabolism. These alterations can affect the availability of structural lipids for the synthesis of membranes, the synthesis and degradation of lipids that contribute to energy homeostasis and the abundance of lipids with signalling functions. Changes in lipid metabolism can affect numerous cellular processes, including cell growth, proliferation, differentiation and motility. This review will examine some of the alterations in lipid metabolism that have been reported in cancer, at both cellular and organismal levels, and discuss how they contribute to different aspects of tumourigenesis.
1,105 citations