P53 a Jack of all trades but master of none

Department of Pathology and Helen Diller Family Comprehensive Cancer Centre, University of California San Francisco, 513 Parnassus Avenue, Room HSW-450A, UCSF Box 0502, San Francisco, California 94143-0502, USA.
Nature Reviews Cancer (Impact Factor: 37.4). 09/2009; 9(11):821-9. DOI: 10.1038/nrc2728
Source: PubMed


Cancers are rare because their evolution is actively restrained by a range of tumour suppressors. Of these p53 seems unusually crucial as either it or its attendant upstream or downstream pathways are inactivated in virtually all cancers. p53 is an evolutionarily ancient coordinator of metazoan stress responses. Its role in tumour suppression is likely to be a relatively recent adaptation, which is only necessary when large, long-lived organisms acquired the sufficient size and somatic regenerative capacity to necessitate specific mechanisms to reign in rogue proliferating cells. However, such evolutionary reappropriation of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor.

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    • "P53, one of the most famous transcription factors, has been documented to be an important tumor suppressor7. The p53 thwarts tumorigenesis by its central monitor role of the cellular stress response pathway8. "
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    ABSTRACT: Recently, a functional polymorphism in KITLG, rs4590952, was identified to be associated with testicular cancer susceptibility through increasing the p53-dependent KITLG expression and disrupting the function of p53. We performed a hospital-based case-control study, including 1241 breast cancer (BC) patients and 1259 cancer-free controls, to investigate the role of this polymorphism in the risk of BC in Chinese Han population. However, no significant association between rs4590952 and BC risk was identified in allelic model with the odds ratio (OR) of 1.04 (95% confidence interval (CI) = 0.73-1.46, P = 0.839) or in any other genetic models. When performed stratified analysis according to the Estrogen Receptor (ER) and Progesterone Receptor (PR) status, rs4590952 was neither associated with ER+/PR+ nor ER-PR- subgroups. Our results suggested that rs4590952 was not associated with the risk of BC in Chinese population, implying that heterogeneous distinct mechanisms might exist in the etiology of different cancers.
    Scientific Reports 09/2014; 4:6371. DOI:10.1038/srep06371 · 5.58 Impact Factor
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    • "Under stressed conditions, p53 is activated in response to diverse intrinsic and extrinsic signals, such as DNA damage, oncogene activation, and hypoxia. As a sequence-specific transcription factor, the activated p53 acts directly on cancer-associated pathways to suppress tumor progression by modulating cell-cycle arrest, senescence, apoptosis, angiogenesis, or invasion and metastasis [41–43]. There are also demonstrations showing that p53 is involved in the regulation of DNA repair, oxidative stress, energy metabolism, and differentiation [44–48]. "
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    ABSTRACT: During the past ten years, microRNAs (miRNAs) have been shown to play a more significant role in the formation and progression of cancer diseases than previously thought. With an increase in reports about the dysregulation of miRNAs in diverse tumor types, it becomes more obvious that classic tumor-suppressive molecules enter deep into the world of miRNAs. Recently, it has been demonstrated that a typical tumor suppressor p53, known as the guardian of the genome, regulates some kinds of miRNAs to contribute to tumor suppression by the induction of cell-cycle arrest and apoptosis. Meanwhile, miRNAs directly/indirectly control the expression level and activity of p53 to fine-tune its functions or to render p53 inactive, indicating that the interplay between p53 and miRNA is overly complicated. The findings, along with current studies, will underline the continuing importance of understanding this interlocking control system for future therapeutic strategies in cancer treatment and prevention.
    BioMed Research International 09/2014; 2014:749724. DOI:10.1155/2014/749724 · 2.71 Impact Factor
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    • "The final example, TP53/p53 serves to show the value of integrating relative expression data with pre-existing genetic information. This tumor suppressor and master regulator of the cell cycle is frequently mutated or deleted in tumors [17, 18]. This analysis confirmed the relative lack of p53 expression in p53-null HL60 cells. "
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    ABSTRACT: Background Development of cancer therapeutics partially depends upon selection of appropriate animal models. Therefore, improvements to model selection are beneficial. Results Forty-nine human tumor xenografts at in vivo passages 1, 4 and 10 were subjected to cDNA microarray analysis yielding a dataset of 823 Affymetrix HG-U133 Plus 2.0 arrays. To illustrate mining strategies supporting therapeutic studies, transcript expression was determined: 1) relative to other models, 2) with successive in vivo passage, and 3) during the in vitro to in vivo transition. Ranking models according to relative transcript expression in vivo has the potential to improve initial model selection. For example, combining p53 tumor expression data with mutational status could guide selection of tumors for therapeutic studies of agents where p53 status purportedly affects efficacy (e.g., MK-1775). The utility of monitoring changes in gene expression with extended in vivo tumor passages was illustrated by focused studies of drug resistance mediators and receptor tyrosine kinases. Noteworthy observations included a significant decline in HCT-15 colon xenograft ABCB1 transporter expression and increased expression of the kinase KIT in A549 with serial passage. These trends predict sensitivity to agents such as paclitaxel (ABCB1 substrate) and imatinib (c-KIT inhibitor) would be altered with extended passage. Given that gene expression results indicated some models undergo profound changes with in vivo passage, a general metric of stability was generated so models could be ranked accordingly. Lastly, changes occurring during transition from in vitro to in vivo growth may have important consequences for therapeutic studies since targets identified in vitro could be over- or under-represented when tumor cells adapt to in vivo growth. A comprehensive list of mouse transcripts capable of cross-hybridizing with human probe sets on the HG-U133 Plus 2.0 array was generated. Removal of the murine artifacts followed by pairwise analysis of in vitro cells with respective passage 1 xenografts and GO analysis illustrates the complex interplay that each model has with the host microenvironment. Conclusions This study provides strategies to aid selection of xenograft models for therapeutic studies. These data highlight the dynamic nature of xenograft models and emphasize the importance of maintaining passage consistency throughout experiments. Electronic supplementary material The online version of this article (doi: 10.1186/1471-2164-15-393) contains supplementary material, which is available to authorized users.
    BMC Genomics 05/2014; 15(1):393. DOI:10.1186/1471-2164-15-393 · 3.99 Impact Factor
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