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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    • "This phenomenon is explained by an intrinsic, fail-safe mechanism whereby genetic events that stimulate cell cycle progression , like overexpression of Myc, sensitize cells to selfdestruct by triggering apoptosis. This concept can explain our inability to induce tumors by overexpressing Myc in mice with intact Tp53 because oncogene-induced apoptosis is often mediated by upregulated expression of Tp53[22]. As a surrogate for Tp53 loss, we expressed Bcl-2, a general and potent suppressor of apoptosis that is highly expressed in human medulloblastomas, in combination with Myc by RCAS transfer in Ntv-a mice[23,24]. "
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    ABSTRACT: A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times. Genetically engineered mouse models have revealed important insights into the pathogenesis of medulloblastoma and served as preclinical testing platforms for new therapies. Here we report a new mouse model of Myc-driven medulloblastoma, in which tumors arise in situ after retroviral transfer and expression of Myc in Nestin-expressing neural progenitor cells in the cerebella of newborn mice. Tumor induction required concomitant loss of Tp53 or overexpression of the antiapoptotic protein Bcl-2. Like Myc-driven medulloblastomas in humans, the tumors induced in mice by Myc + Bcl-2 and Myc − Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. The fact that Myc − Tp53 tumors arose only in Tp53 −/− mice, coupled with the inefficient germline transmission of the Tp53-null allele, made retroviral transfer of Myc + Bcl-2 a more practical method for generating LCA medulloblastomas. The high rate of spinal metastasis (87 % of brain tumor–bearing mice) will be an asset for testing new therapies that target the most lethal aspect of medulloblastoma.
    Full-text · Article · Oct 2015 · Journal of Neuro-Oncology
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    • "The selective protection of normal tissues is possible because this strategy requires normal functioning p53 (Ganapathy et al., 2014aGanapathy et al., , 2014b ). Essentially all of the cancer cells have either mutated or dysfunctional p53 and therefore are not protected (Junttila and Evan, 2009). Importantly, it has been demonstrated that DNA damaging agent-induced p53 activity is inconsequential to the tumor suppressor function of p53, negating the concern that suppression of p53, even though temporary, could contribute to tumor development or progression (Christophorou et al., 2005Christophorou et al., , 2006). "
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    ABSTRACT: p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy. This trial is registered in Identifier: NCT01428128.
    Full-text · Article · Sep 2015 · Molecular oncology
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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.
    Full-text · Article · Sep 2014 · Scientific Reports
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