Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med

McGill Cancer Centre, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Journal of Molecular Medicine (Impact Factor: 5.11). 12/2007; 85(11):1175-86. DOI: 10.1007/s00109-007-0221-2
Source: PubMed


The p53 tumor suppressor protein has long been recognized as the central factor protecting humans from cancer. It has been famously dubbed "the guardian of the genome" due to its ability to respond to genotoxic stress, such as DNA damage and other stress signals, and to protect the genome by inducing a variety of biological responses including DNA repair, cell cycle arrest, and apoptosis. However, the tumor suppressive effects of p53 go far beyond its roles in mediating these three processes. There is growing evidence that p53 also exerts its effects on multiple aspects of tumor formation, including suppression of metastasis and, as summarized in this review, inhibition of new blood vessel development (angiogenesis). The p53 protein has been shown to limit angiogenesis by at least three mechanisms: (1) interfering with central regulators of hypoxia that mediate angiogenesis, (2) inhibiting production of proangiogenic factors, and (3) directly increasing the production of endogenous angiogenesis inhibitors. The combination of these effects allows p53 to efficiently shut down the angiogenic potential of cancer cells. Inactivation of p53, which occurs in approximately half of all tumors, reverses these effects; as a consequence, tumors carrying p53 mutations appear more vascularized and are often more aggressive and correlate with poor prognosis for treatment. Thus, the loss of functional p53 during tumorigenesis likely represents an essential step in the switch to an angiogenic phenotype that is displayed by aggressive tumors.

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    • "p53 controls cell cycle, apoptosis, DNA repair, senescence, angiogenesis, cellular metabolism, and innate immunity.[111213] "
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    ABSTRACT: Background: Fragile histidine triad (FHIT) is considered as a member of the histidine triad (HIT) nucleotide-binding protein superfamily regarded as a putative tumor suppressor executing crucial role in inhibiting p53 degradation by MDM2. Accumulating evidences indicate FHIT interaction with p53 or MDM2; however, there is no certain study deciphering functional domains of FHIT involving in the interaction with MDM2 and/or p53. In this regard, such evident interaction can spring in mind determining important domains of FHIT binding to MDM2 with regard to p53. Materials and Methods: Since there were not any previous studies appraising complete three-dimensional structures of target molecules, molecular modeling was carried out to construct three-dimensional models of full FHIT, MDM2, P53 and also FHIT segments. Truncated structures of FHIT were created to reveal critical regions engaging in FHIT interaction. Results: Given the shape and shape/electrostatic total energy, FHIT structures (β1-5), (β3-7, α1), and (β5-7, α1) appeared to be better candidates than other structures in interaction with full MDM2. Furthermore, FHIT structures (β6-7), (β6-7, α1), (β4-7, α1) were considered to be better than other structures in interaction with p53. FHIT truncates that interact with MDM2 presented lower energy levels than FHIT truncates interacting with p53. Conclusion: These findings are beneficial to understand the mechanism of the FHIT-MDM2-p53 complex activation for designing inhibitory compounds.
    Full-text · Article · Aug 2014
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    • "In response to cellular stress such as DNA damage, oncogene activation, transcriptional inhibition, and hypoxia, tumor suppressor p53 is activated and expressed, and acts as a transcription factor to induce its target genes [1], thereby playing a central role in the regulation of DNA repair, cell cycle, apoptosis, senescence, and angiogenesis [2-4]. Its major target genes include proapoptotic genes Bax, Puma and Noxa, cell cycle regulator p21, and the senescence-inducing gene Plasminogen activator inhibitor 1 [5]. "
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    ABSTRACT: At high cytotoxic concentrations, actinomycin D (ActD) blocks transcription, decreasing levels of MDM2 and thus causing p53 stabilization. At low cytostatic concentrations, ActD causes ribosomal stress, which decreases MDM2 activity, resulting in p53 stabilization and activation. ActD can thus be used for p53-based cyclotherapy. We analyzed pathways mediating ActD-induced p53 expression. Inhibitors (LY294002, wortmannin, and deguelin) of phosphatidylinositol 3-kinases (PI3K) and AKT, but not inhibitors of MEK1/2, JNK, and p38-MAPK abolished the ActD-induced p53 expression in diverse cell types. RNA interference further supported these results. When AKT was downregulated by small hairpin RNA-AKTs, ActD-induced p53 expression was significantly decreased. ActD caused AKT phosphorylation at Ser473, indicating full activation of AKT. The potential for cancer therapy is discussed.
    Full-text · Article · Jan 2014 · Oncotarget
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    • "The tumour suppressor protein p53 plays a pivotal role in DNA repair, cell cycle regulation and apoptosis [1] [2]. Moreover, this protein is an attractive anticancer therapeutic target because it can be functionally activated to eradicate tumour. "

    Full-text · Article · Jan 2014 · European Journal of Medicinal Chemistry
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