Characterization and Functional Analysis of Mutant P53 Secretome in Human Cancer
Title | Characterization and Functional Analysis of Mutant P53 Secretome in Human Cancer PDF eBook |
Author | Reshma Shakya |
Publisher | |
Pages | 478 |
Release | 2016 |
Genre | Cancer |
ISBN |
Among several genetic alterations in human cancer, mutations in the TP53 tumour suppressor gene represent the most common, occurring in approximately 50% of all human cancers. The majority of these mutations in p53 are missense mutations, resulting in cancer cells expressing stable, full-length mutated p53 proteins. Missense mutant p53's exhibit loss of tumour suppressive property of wild-type p53, dominant negative effects that can inactivate any wild-type p53 protein, and gain-of-function (GOF) properties that promote tumour progression and metastasis. Evidence suggests that cancer cells depend on the sustained expression of mutant p53 GOF. Thus, identifying the common downstream factor that drive mutant p53 GOF can provide an attractive approach to therapeutically target mutant p53 expressing tumours. This thesis presents the study of the characterization and functional analysis of mutant p53 secreted factors called "the mutant p53 secretome". In particular, the thesis aims at identifying the critical secreted effector of mutant p53 GOF that can serve as a potential therapeutic target for treatment of mutant p53 expressing tumours. Furthermore, the thesis investigates the association of the identified factor within the secretome with clinical parameters such as patient's survival. This thesis makes several original contributions to the field of cancer research, which are briefed below. Firstly, the mutant p53 induced secretome was characterized using quantitative proteomics of conditioned medium from mutant p53 expressing inducible H1299 human lung cancer cells. The majority of the identified secreted proteins were the transcriptional targets influenced by mutant p53. Alpha-1 antitrypsin (A1AT) was selected for further investigation, as it was the protein showing the highest expression in the mutant p53 secretome. The role of A1AT in driving the oncogenic activity of mutant p53 in human lung cancer cells was explored. A1AT was shown to drive mutant p53 induced invasion in lung cancer cell lines. Ablation of A1AT using antibodies and gene knockdown approaches inhibited the mutant p53 driven invasion, providing a rational to investigate the development of antibody-based cancer therapies that target A1AT. The clinical association of A1AT was further investigated in tissue microarray (TMA) samples of lung adenocarcinoma (ADC) patients. Mutant p53 expression was shown to correlate with A1AT, which validates in vivo that A1AT is a bonafide target of mutant p53. Furthermore, elevated expression of A1AT was demonstrated to correlate with increased local invasion and poor prognosis of lung ADC patients. Mutant p53 is reported to function as an aberrant transcription factor that can interact with other transcription factors to reprogram the cellular transcriptome of cancer cells. The mechanism of regulation of A1AT by mutant p53 was confirmed to involve p63. The role of A1AT in driving the mutant p53 induced invasive behavior of breast cancer cells was also explored, and a relationship of A1AT with p53 status and with different subtypes of breast cancer was established. In p53 mutant basal-like subtypes, A1AT expression was shown to drive invasion and treatment with anti-A1AT antibodies inhibited invasion. This suggests that the A1AT-targeted are potential therapies in various cancer types and its regulation in breast cancer may also extend beyond p53. Collectively, these studies provide new insights into the invasive behavior of mutant p53 that are manifested through aberrant secretion of extracellular proteins. The identification of A1AT as a critical and indispensable effector of mutant p53 gain-of-function offers a new therapeutic options for treatment of p53 mutant tumours. The findings in this thesis involve significant elements of novelty describing how mutant p53 influences the cellular secretome.
Development of Yeast as an In Vivo Test Tube to Characterize a Broad Spectrum of P53 Mutations Associated with Breast Cancer
Title | Development of Yeast as an In Vivo Test Tube to Characterize a Broad Spectrum of P53 Mutations Associated with Breast Cancer PDF eBook |
Author | |
Publisher | |
Pages | 0 |
Release | 2002 |
Genre | |
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The p53 tumor suppressor protein is an inducible, sequence-specific transcription factor capable of modulating the expression of more than 100 genes in human cells to coordinate different cellular responses to stress. The p53 pathway is altered in nearly all human cancers and p53 mutant proteins with amino acid changes in the DNA binding domain are aberrantly expressed in nearly 50% of tumors. We developed a system in the yeast Saccharomyces cerevisiae that addresses p53 transactivation capacity from 26 different p53 Response Elements (REs) in a constant chromatin structure and that provides for detailed functional analysis of p53 mutant alleles. We applied this method in trying to elucidate the mechanisms that regulate differential transactivation by p53 and determined the functional fingerprints of many p53 mutants including a group of novel alleles that were reported in familial breast cancer. Interestingly, we observed that among 1300 different amino acid changes detected in tumors, many do not result simply in loss of function but instead alter the ability to transactivate from the various target sequences. Our results suggest that the actual functional status of p53 alleles expressed in tumor cells, not simply whether or not there is a mutation, may correlate with clinical outcome. The yeast functional assay offers a practical means to develop ap53 mutant functionality database that is likely to become valuable in predicting tumor aggressiveness and responsiveness to therapy.
Human Tumor-Derived p53 Mutants: A Growing Family of Oncoproteins
Title | Human Tumor-Derived p53 Mutants: A Growing Family of Oncoproteins PDF eBook |
Author | Ygal Haupt |
Publisher | Frontiers Media SA |
Pages | 99 |
Release | 2016-08-10 |
Genre | Medicine (General) |
ISBN | 2889199614 |
TP53 gene mutations are present in more than half of all human cancers. The resulting proteins are mostly full-length with a single amino acid change and are abundantly expressed in cancer cells. Some of the mutant p53 proteins gain oncogenic functions (GOF) through which it actively contribute to the aberrant cell proliferation, increased resistance to apoptotic stimuli and ability to metastasize. Gain of function mutant p53 proteins can transcriptionally regulate the expression of a large plethora of target genes. This mainly occurs through the formation of oncogenic transcriptional competent complexes that include mutant p53 protein, known transcription factors, posttranslational modifiers and scaffold proteins. Mutant p53 protein can also transcriptionally regulate the expression of microRNAs, small non-coding RNAs that regulate gene expression at the posttranscriptional level. Each microRNA can putatively target the expression of hundred mRNAs and consequently impact on many cellular functions. Thus, gain of function mutant p53 proteins can exert their oncogenic activities through the modulation of both non-coding and coding regions of human genome. Over the past 3 decades, the regulation of p53 has been extensively studied. However, the regulation of mutant p53 remained largely unexplored. This snapshot focuses on recent discovery of mutant p53 GOF and regulation.
Genes and Cancer
Title | Genes and Cancer PDF eBook |
Author | Karol Sikora |
Publisher | Wiley |
Pages | 364 |
Release | 1990-10-26 |
Genre | Medical |
ISBN | 9780471925835 |
This work serves as an introduction to the applications of molecular biology in the field of oncology. It provides a basic understanding of the genetic events involved in fully developed human cancer, including research into inherited and acquired gene defects initiating new neoplasms and the subsequent genetic alterations involved in tumor progression. Some of the specific topics explored include gene control, molecular therapy and antibodies, drug resistance, growth factors and receptors, and tumor biology. While intended primarily as an advanced text for oncologists, postgraduate molecular geneticists and molecular biologists, the book will certainly be of interest to other researchers who frequently encounter cancer in their practice.
Cancer Models
Title | Cancer Models PDF eBook |
Author | Michael Breitenbach |
Publisher | |
Pages | 0 |
Release | 2019 |
Genre | |
ISBN |
This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.
Frontiers in Cancer Research
Title | Frontiers in Cancer Research PDF eBook |
Author | Carlo C. Maley |
Publisher | Springer |
Pages | 266 |
Release | 2016-11-21 |
Genre | Medical |
ISBN | 1493964607 |
This is the ideal book for anyone contemplating starting a career in, or shifting their career to, studying the dynamics that drive cancer progression and its response to therapy. Topics include the theory and population genetics of cancers, genetic diversity within tumors (intra-tumor heterogeneity), understanding how mutant clones expand in tissues, the role of cancer stem cells in the dynamics of tumors, the evolution of metastasis, and how to improve cancer therapy by addressing the evolution of cancers in response to our interventions. There are also chapters on the patterns of cancer susceptibility in humans due to a mismatch between our modern environment and the environment in which our ancestors evolved, as well as a chapter on the evolution of cancer suppression mechanisms that have evolved in different species, particularly the large long-lived animals like elephants and whales that are better at suppressing cancers than humans. This book serves as a primer on the evolutionary and ecological theory of cancer- the framework upon which all the details of cancer may be hung. It is ideal for oncologists and cancer researchers interested in evolutionary theory, and evolutionary biologists and ecologists interested in gaining insights into cancer development and prevention.
Exosomes, Stem Cells and MicroRNA
Title | Exosomes, Stem Cells and MicroRNA PDF eBook |
Author | Karl L. Mettinger |
Publisher | Springer |
Pages | 160 |
Release | 2018-05-12 |
Genre | Science |
ISBN | 3319744704 |
This volume provides insight into the pivotal roles of stem cells, exosomes and other microvesicles in biofunction and molecular mechanisms and their therapeutic potential in translational nanomedicine. It further highlights evidence from recent studies as to how stem cell derived exosomes and microRNAs may restore and maintain tissue homeostasis, enable cells to recover critical cellular functions and begin repair regeneration. These early studies in animal models of aging also show evidence of improved immune, cardiovascular and cognitive functions as well as improved health span and life span. The use of exosomes from body fluids to define specific biomarkers for various tumors may also clear the path to patient-targeted treatments by developing exosome-derived microRNA based cancer therapeutics. It is essential reading for graduate students, research fellow and biomedical researchers in academia or the pharmaceutical or biotech industries.