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Query: UMLS:C0009443 (cold)
 92,137 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the course of tumorigenesis, cells acquire a number of alterations that contribute to the acquisition of the malignant phenotype, allowing them to survive and flourish in increasingly hostile environments. Cancer cells can be characterized by perturbations in the control of cell proliferation and growth, resistance to death, and alterations in their interactions with the microenvironment. Underpinning many of these changes are shifts in metabolism that allow cancer cells to use alternative pathways for energy production and building the macromolecules necessary for growth, as well as regulating the generation of signaling molecules such as reactive oxygen species (ROS). In the past few years, it became clear that p53, the most studied, if not most important, tumor suppressor protein, can also directly control metabolic traits of cells.
Cold Spring Harb Perspect Biol 2010 Apr
PMID:p53 regulation of metabolic pathways. 2045 43

Studies in mice have yielded invaluable insight into our understanding of the p53 pathway. Mouse models with activated p53, no p53, and mutant p53 have queried the role of p53 in development and tumorigenesis. In these models, p53 is activated and stabilized via redundant posttranslational modifications. On activation, p53 initiates two major responses: inhibition of proliferation (via cell-cycle arrest, quiescence, senescence, and differentiation) and induction of apoptosis. Importantly, these responses are cell-type and tumor-type-specific. The analysis of mutant p53 alleles has established a gain-of-function role for p53 mutants in metastasis. The development of additional models that can precisely time the oncogenic events in single cells will provide further insight into the evolution of tumors, the importance of the stroma, and the cooperating events that lead to disruption of the p53 pathway. Ultimately, these models should serve to study the effects of novel drugs on tumor response as well as normal homeostasis.
Cold Spring Harb Perspect Biol 2010 Apr
PMID:Mouse models of p53 functions. 2045 44

The tumor suppressor p53 is a master sensor of stress that controls many biological functions, including implantation, cell-fate decisions, metabolism, and aging. In response to a defined stress signal such as gamma radiation, the response of p53 is heterogeneous in vivo. Like a complex barcode, the ability of p53 to function as a central hub that integrates defined stress signals into decisive cellular responses, in a time- and cell-type dependent manner, is facilitated by the extraordinary complexity of its regulation. Key components of this barcode are the autoregulation loops, which positively or negatively regulate p53's activities. Thus, this article focuses on reviewing our current understanding of how autoregulation loops formed between p53 and how its transcriptional targets regulate the activities of p53 at a variety of levels, through mdm2-dependent and -independent pathways. Knowing that a large number of autoregulation loops exist that influence p53's activity, our future challenge is to elucidate which of these play a central role in regulating p53, under which conditions, in response to what stress, and at which particular stage of our lives. Such knowledge may ultimately lead to the development of more effective anticancer therapeutics.
Cold Spring Harb Perspect Biol 2010 May
PMID:Tied up in loops: positive and negative autoregulation of p53. 2045 57

The p53 tumor suppressor pathway is central both in reducing cancer frequency in vertebrates and in mediating the response of commonly used cancer therapies. This article aims to summarize and discuss a large body of evidence suggesting that the p53 pathway harbors functional inherited single-nucleotide polymorphisms (SNPs) that affect p53 signaling in cells, resulting in differences in cancer risk and clinical outcome in humans. The insights gained through these studies into how the functional p53 pathway SNPs could help in the tailoring of cancer therapies to the individual are discussed. Moreover, recent work is discussed that suggests that many more functional p53 pathway SNPs are yet to be fully characterized and that a thorough analysis of the functional human genetics of this important tumor suppressor pathway is required.
Cold Spring Harb Perspect Biol 2010 May
PMID:Single-nucleotide polymorphisms in the p53 signaling pathway. 2045 58

The p53 protein is modified by as many as 50 individual posttranslational modifications. Many of these occur in response to genotoxic or nongenotoxic stresses and show interdependence, such that one or more modifications can nucleate subsequent events. This interdependent nature suggests a pathway that operates through multiple cooperative events as opposed to distinct functions for individual, isolated modifications. This concept, supported by recent investigations, which provide exquisite detail as to how various modifications mediate precise protein-protein interactions in a cooperative manner, may explain why knockin mice expressing p53 proteins substituted at one or just a few sites of modification typically show only subtle effects on p53 function. The present article focuses on recent, exciting progress and develops the idea that the impact of modification on p53 function is achieved through collective and integrated events.
Cold Spring Harb Perspect Biol 2009 Dec
PMID:Posttranslational modification of p53: cooperative integrators of function. 2045 58

The p53 family of genes (p53, p63, and p73) is conserved over evolutionary time scales. Although the functions of p53 gene and its protein as a tumor suppressor have been firmly established, the earliest functions for the p53 ancestral genes in worms and flies are to ensure germ-line genomic integrity and the fidelity of the developmental process. In vertebrates, the p53 family of genes retains those functions in germ-line genomic integrity but have added important functions in regulation of reproduction. Loss of the p53, p63, or p73 genes in female mice leads to a significant decrease of fertility. The p53 gene product regulates maternal reproduction at the implantation stage of the embryo. p63 and p73 play important roles in monitoring the genomic quality of oocytes. The p53 pathway appears to play a similar role in human fertility. In humans, certain alleles containing a functional single-nucleotide polymorphism (SNP) in the p53 pathway are under positive evolutionary selection. Selected alleles of these SNPs in the p53 pathway are associated with decreased fertility. This important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway. These observations provide a good possible example of antagonistic pleiotrophy for fertility, tumor suppression, and longevity.
Cold Spring Harb Perspect Biol 2009 Dec
PMID:The role of p53 gene family in reproduction. 2045 59

The p53 tumor suppressor is a multifaceted transcription factor that responds to a diverse array of stresses that include DNA damage and aberrant oncogene signaling. On activation, p53 prevents the emergence of cancer cells by initiating cell cycle arrest, senescence (terminal cell cycle arrest), or apoptosis. Although its role in assuring longevity by suppressing cancer is well established, recent studies obtained largely from genetically engineered mouse models suggest that p53 may regulate longevity and aging. In some contexts, it appears that altered p53 activity may enhance longevity, and in others, it appears to suppress longevity and accelerate aging phenotypes. Here, we discuss how genetically engineered mouse models have been used to explore antiproliferative functions of p53 in cancer suppression and how mouse models with altered aging phenotypes have shed light on how p53 might influence the aging process.
Cold Spring Harb Perspect Biol 2009 Dec
PMID:Using mice to examine p53 functions in cancer, aging, and longevity. 2045 60

Thirty years of research on the p53 family of genes has generated almost fifty thousand publications. The first of these papers detected the p53 protein associated with a viral oncogene product in transformed cells and tumors and focused the field on cancer biology. Subsequent manuscripts have shown a wide variety of functions for the p53 family of genes and their proteins. These proteins are involved in reproduction, genomic repair, fidelity and recombination, the regulation of metabolic processes, longevity, surveillance of the stability of development, the production of stem cells and changes in epigenetic marks, the development of the nervous system (p73), the immune system (p73) and skin (p63), as well as the better known roles for the family in tumor suppression. The p53 family of genes has been found in the modern day ancestors of organisms with over one billion years of evolutionary history where they play a role in germ-line fidelity over that time span. As the body plan of the vertebrates emerged with the regeneration of tissues by stem cells over a lifetime, the p53 gene and its protein were adapted to be a tumor suppressor of somatic stem and progenitor cells complementing its' past functions in the germ line. Because the p53 family of genes has played a role in germ-line fidelity and preservation of the species, even in times of stress, these genes have been under constant selection pressure to change and adapt to new situations. This has given rise to this diversity of functions all working to preserve homeostatic processes that permit growth and reproduction in a world that is constantly challenging the fidelity of information transfer at each generation. The p53 family of gene products has influenced the rates of evolutionary change, just as evolutionary changes have altered the p53 family and its functions.
Cold Spring Harb Perspect Biol 2010 Dec
PMID:p53 Research: the past thirty years and the next thirty years. 2046 1

Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene therapy using wild-type p53, delivered by adenovirus vectors, is now in widespread use in China. Other biologic approaches include the development of oncolytic viruses designed to replicate and kill only p53 defective cells and also the development of siRNA and antisense RNA's that activate p53 by inhibiting the function of the negative regulators Mdm2, MdmX, and HPV E6. The altered processing of p53 that occurs in tumor cells can elicit T-cell and B-cell responses to p53 that could be effective in eliminating cancer cells and p53 based vaccines are now in clinical trial. A number of small molecules that directly or indirectly activate the p53 response have also reached the clinic, of which the most advanced are the p53 mdm2 interaction inhibitors. Increased understanding of the p53 response is also allowing the development of powerful drug combinations that may increase the selectivity and safety of chemotherapy, by selective protection of normal cells and tissues.
Cold Spring Harb Perspect Biol 2010 Sep
PMID:p53-based cancer therapy. 2046 3

p73 and p63 are two homologs of the tumor suppressive transcription factor p53. Given the high degree of structural similarity shared by the p53 family members, p73 and p63 can bind and activate transcription from the majority of the p53-responsive promoters. Besides overlapping functions shared with p53 (i.e., induction of apoptosis in response to cellular stress), the existence of extensive structural variability within the family determines unique roles for p63 and p73. Their crucial and specific functions in controlling development and differentiation are well exemplified by the p63 and p73 knockout mouse phenotypes. Here, we describe the contribution of p63 and p73 to human pathology with emphasis on their roles in tumorigenesis and development.
Cold Spring Harb Perspect Biol 2010 Sep
PMID:p63 and p73, the ancestors of p53. 2048 88


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