Structural and Functional Basis for Therapeutic Modulation of p53 Signaling

Department of Medicine, The Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Clinical Cancer Research (Impact Factor: 8.72). 11/2008; 14(20):6376-86. DOI: 10.1158/1078-0432.CCR-08-1526
Source: PubMed


Effective modulation of structural features and/or functional properties of the major tumor suppressor p53 as a wild-type or cancer-associated mutant protein represents a major challenge in drug development for cancer. p53 is an attractive target for therapeutic design because of its involvement as a mediator of growth arrest and apoptosis after exposure to chemoradiotherapy and/or radiotherapy. Although most clinically used cytotoxic agents target stabilization of wild-type p53, there are a number of approaches that hold promise for reactivation of mutant p53. On the other hand, brief blockade of p53 may reduce toxicity from systemic cytotoxic therapy. Screens for restoration of p53 transcriptional responses in p53-deficient cells may provide a functional means to develop anticancer therapeutics. Structure-based modulation continues to hold promise for development of peptides or small molecules capable of modulation of either wild-type or mutant p53 proteins.

2 Reads
  • Source
    • "Cisplatin-induced DNA damage is the major cause of cell injury and death during chemotherapy , whereas p53 plays a major role in cisplatin-induced cell death (Cepeda et al., 2007; Wang and Lippard, 2005). The p53 tumor suppressor protein induces apoptosis in response to DNA damage and oncogene activation (Bassett et al., 2008). Pharmacologic or genetic repression of p53 transcription reduced cisplatin-induced apoptosis and renal injury (Molitoris et al., 2009; Wei et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage including DNA fragmentation, up regulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidants enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidants enzymes.
    Full-text · Article · Jan 2015 · Food and Chemical Toxicology
  • Source
    • "Nutlin-3a, which activates p53 by antagonizing its negative regulator MDM2, also enhanced PLK2 expression (Fig 3B) (Bassett et al, 2008). Taken together, these results indicate that PLK2 expression is a relevant indicator of p53 functionality and the integrity of the DNA-damage response pathway in B-CLL cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The functional evaluation of ataxia telangiectasia mutated (ATM) and p53 was recently developed in B-cell chronic lymphocytic leukaemia (B-CLL), a disease in which the response to DNA damage is frequently altered. We identified a novel biomarker of chemosensitivity based on the induction of DNA damage by the purine nucleoside analogues (PNA) fludarabine and 2-chlorodeoxyadenosine (CdA). Using genome-wide expression profiling, it was observed that, in chemosensitive samples, PNA predominantly increased the expression of p53-dependent genes, among which PLK2 was the most highly activated at early time points. Conversely, in chemoresistant samples, p53-dependent and PLK2 responses were abolished. Using a quantitative real time polymerase chain reaction, we confirmed that PNA dose- and time-dependently increased PLK2 expression in chemosensitive but not chemoresistant B-CLL samples. Analysis of a larger cohort of B-CLL patients showed that cytotoxicity induced by PNA correlated well with PLK2 mRNA induction. Interestingly, we observed that failure to up-regulate PLK2 following PNA and chemoresistance were not strictly correlated with structural alterations in the TP53 gene. In conclusion, we propose that testing PLK2 activation after a 24-h incubation with PNA could be used to investigate the functional integrity of DNA damage-response pathways in B-CLL cells, and predict clinical sensitivity to these drugs.
    Full-text · Article · Sep 2009 · British Journal of Haematology
  • Source
    • "in protein - protein interactions in signal transduction ; a sequence - specific DNA binding domain that binds to consen - sus sequences often in the promoter area of target genes ; an oligomerization domain that regulates the tetramerization of TP53 protein ; and finally a C - terminal region that binds DNA non - specifically and senses damaged DNA ( Fig 1 ) . Three nuclear localization signals that tag and target the TP53 protein to the nucleus are also located in this area ( Malkin , 2001 ; Bassett et al , 2008 ) . Extensive analyses of somatic TP53 mutations and their effects on gene function have been undertaken since the discovery of TP53 in 1979 ( Malkin , 2001 ) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The tumour suppressor TP53 (previously termed p53) mediates a pathway that is considered to be one of the most important mechanisms in the maintenance of genomic stability. The function of TP53 can be abrogated by genomic deletion, mutation, or deregulation of upstream and downstream participants in the TP53 pathway. While aberrations of TP53 are widely prevalent in non-haematological malignancies (over 60%), they are present in much lower frequency in haematological malignancies (<20%). Nevertheless, in those cases where TP53 function or expression is aberrant, correlation with inferior clinical outcome (such as overall survival and progression or transformation) has generally been strong. In this review, we focus our discussion on the relationship between TP53 and lymphoid malignancies as defined by the World Health Organization. Specifically, we examine the prevalence of TP53 aberrations and their prognostic significance in various types of lymphoid cancer. Next, we discuss the various mechanisms of TP53 inactivation. Finally, we summarize progress in the use of recent therapeutic modalities that target TP53.
    Preview · Article · Jun 2009 · British Journal of Haematology
Show more