Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intra- and intercellular communication in or between cells allows adaptation to changes in the environment. Formation of reactive oxygen (ROS) and nitrogen (RNS) species in response to external insults gained considerable attention in provoking cell demise along an apoptotic subroute of cell death, thus attributing radical formation to pathologies. In close association, stabilization of the tumor suppressor p53 and activation of caspases convey proapoptotic signaling. Complexity was added with the notion that ROS and RNS signals overlap and/or produce synergistic as well as antagonistic effects. With respect to nitric oxide (NO) signaling, it became clear that the molecule is endowed with pro- or antiapoptotic signaling capabilities, depending to some extend on the concentration and cellular context, i.e., ROS generation. Here, some established concepts are summarized that allow an explanation of p53 accumulation under the impact of NO and an understanding of NO-evoked cell protection at the level of caspase inhibition, cyclic GMP formation, or expression of antiapoptotic proteins. In addition, the overlapping sphere of ROS and RNS signaling is recapitulated to appreciate cell physiology/pathology with the notion that marginal changes in the flux rates of either NO or superoxide may shift vital signals used for communication and cell survival into areas of pathology in close association with apoptosis/necrosis.
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PMID:The intimate relation between nitric oxide and superoxide in apoptosis and cell survival. 1570 97

The diatomic radical nitric oxide has been the focus of numerous studies involved with every facet of cancer. It has been implicated in carcinogenesis, progression, invasion, metastasis, angiogenesis, escape from immune surveillance, and modulation of therapeutic response. In recent years, an increasing number of studies have suggested the possible involvement of nitric oxide in multiple cancer types, including melanoma. It is perhaps not surprising that conflicting viewpoints have arisen as to whether nitric oxide is beneficial or deleterious in cancer. However, it has become clear that nitric oxide possesses modulatory properties in a number of signal transduction pathways that depend on concentration and context. Our laboratory has shown that tumor expression of inducible nitric oxide synthase in melanoma patients results in poor survival. Furthermore, we demonstrated that the removal of endogenous nitric oxide in melanoma cell lines led to increased sensitivity to cisplatin-induced apoptosis in a p53-dependent manner. Others have shown anti-apoptotic properties of NO in melanoma cells. However, several studies also suggest that NO can inhibit metastasis and diminish resistance. Despite the apparently conflicting observations, it is evident that NO is involved in melanoma pathology. The purpose of this review is to summarize the current literature relating to the role of NO in cancer with particular emphasis on its relevance to therapeutic resistance in melanoma. Recent evidence suggests the involvement of an intricate and complex interplay between reactive nitrogen species and reactive oxygen species. The importance of nitric oxide and its balance with other oxidative agents in the regulation of cancer cell response to therapies will be discussed. This balance may serve as an important focal point in determining patient response to therapy. The ability to control this balance could significantly influence outcome.
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PMID:NO news is not necessarily good news in cancer. 1581 Aug 75

Actinic keratosis (AK) is a common sun-induced precancerous neoplasm confined to the epidermis. The AK is the initial manifestation of a continuum of clinical and histologic abnormalities that progresses to invasive squamous cell carcinoma (SCC). Bowen's disease, also known as squamous cell carcinoma in situ, represents early SCC confined to the epidermis. More than half of all SCCs contain p53 tumor suppressor gene mutations. Like SCCs, the vast majority of AKs and Bowen's disease lesions are asymptomatic. Each AK and suspicious lesion should be treated before it progresses to invasive SCC. Destructive modalities, such as cryosurgery using liquid nitrogen and electrodesiccation and curettage, usually performed by a dermatologist, are the mainstays of therapy.
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PMID:Premalignant and early squamous cell carcinoma. 1581 19

Nucleostemin is a p53-interactive cell cycle progression factor that shuttles between the nucleolus and nucleoplasm, but it has no known involvement in ribosome synthesis. We found the dynamic properties of nucleostemin differed strikingly from fibrillarin (a protein directly involved in rRNA processing) both in response to rRNA transcription inhibition and in the schedule of reentry into daughter nuclei and the nucleolus during late telophase/early G1. Furthermore, nucleostemin was excluded from the nucleolar domains in which ribosomes are born--the fibrillar centers and dense fibrillar component. Instead it was concentrated in rRNA-deficient sites within the nucleolar granular component. This finding suggests that the nucleolus may be more subcompartmentalized than previously thought. In support of this concept, electron spectroscopic imaging studies of the nitrogen and phosphorus distribution in the nucleolar granular component revealed regions that are very rich in protein and yet devoid of nucleic acid. Together, these results suggest that the ultrastructural texture of the nucleolar granular component represents not only ribosomal particles but also RNA-free zones populated by proteins or protein complexes that likely serve other functions.
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PMID:A nonribosomal landscape in the nucleolus revealed by the stem cell protein nucleostemin. 1585 56

Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link between vanadium and oxidative stress in the etiology of diabetes. The impact of zinc (Zn) on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiology of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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PMID:Metals, toxicity and oxidative stress. 1589 31

Benzo[a]pyrene (B[a]P) is present in environmental pollution and cigarette smoke. B[a]P has been shown to induce apoptosis in hepatoma cells, human B cells, human ectocervical cells, macrophages, and rat lungs. Nitrogen oxides (NOx) are the other important indoor and outdoor air pollutants. Many studies have indicated that NO gas causes lung tissue damage both by its oxidative properties and free radicals. In our previous study we demonstrated that NO gas induced proliferation of human lung fibroblast MRC-5 cells. In this study we showed that NO gas inhibits B[a]P-induced MRC-5 cells apoptosis by cell cycle analysis. Western blot data revealed that NO gas increased the expressions of anti-apoptosis proteins (Bcl-2 and Mcl-1) and decreased the expression of apoptosis proteins (Bax, t-Bid, cytochrome c, FasL, and caspases) after B[a]P treatment. We further clarified that B[a]P-induced MRC-5 cell apoptosis via JNK1/FasL and JNK1/p53 signals. In conclusion, NO gas inhibited B[a]P-induced MRC-5 cells apoptosis via inhibition of JNK1 apoptosis pathway and induction of Bcl-2 and Mcl-1 anti-apoptosis pathway.
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PMID:Gaseous nitrogen oxide repressed benzo[a]pyrene-induced human lung fibroblast cell apoptosis via inhibiting JNK1 signals. 1604 17

The metallic compound cisplatin has been used for many years to treat various human cancers. Here, we describe the cytostatic and cytotoxic properties of a new class of organometallic compounds that contain a ruthenium (II) atom covalently linked to carbon and nitrogen atoms. We found that several ruthenium-derived compounds (RDCs) led to G1 arrest and induced apoptosis in tumor cell lines derived from glioblastomas, neuroblastomas, and lymphoid tumors at least as efficiently as cisplatin. We further analyzed the signaling pathways underlying these effects, and we showed that both RDCs and cisplatin induced p53 and p73 protein levels but with different intensities and kinetics. This accumulation of p53 and p73 proteins correlated with an increase in p21 and Bax expression, two p53 target genes linked to cell growth arrest and apoptosis. However, in contrast to cisplatin-induced apoptosis, overexpression of DeltaNp73, a p53 and p73 dominant-negative isoform, only partly reduced RDC-induced apoptosis, suggesting p53-dependent and p53-independent modes of action. This observation was further confirmed by the ability of RDC to induce apoptosis in p53-/- cells. Altogether, this study highlights key cellular and molecular features of RDCs and suggests that further development of this new class of compounds may contribute to improve future chemotherapeutic protocols.
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PMID:Ruthenium (II)-derived organometallic compounds induce cytostatic and cytotoxic effects on mammalian cancer cell lines through p53-dependent and p53-independent mechanisms. 1616 39

Zinc deficiency is characterized by an attenuation of growth factor signaling pathways and an amplification of p53 pathways. This outcome is facilitated by hypo-phosphorylation of AKT and ERK secondary to zinc deficiency, which are permissive events to the activation of the intrinsic cell death pathway. Low zinc concentrations provide an environment that is also conducive to the production of reactive oxygen/reactive nitrogen species (ROS/RNS) and caspase activation. Additionally, during zinc deficiency endogenous survival pathways such as NF-kappaB are inhibited in their transactivation potential. The above factors contribute to the irreversible commitment of the zinc deficient cell to death.
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PMID:Zinc deficiency-induced cell death. 1622 5

The molecular mechanisms responsible for the cellular effects of the nitrogen-containing bisphosphonate zoledronic acid (Zol) were assessed on several osteosarcoma cell lines differing in their p53 and retinoblastoma (Rb) status. Zol inhibited cell proliferation and increased atypical apoptosis. The Zol effects on proliferation were due to cell cycle arrest in S and G2/M phases subsequent to the activation of the intra-S DNA damage checkpoint with an increase in P-ATR, P-chk1, Wee1, and P-cdc2 levels and a decrease in cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of caspase activation, and it was characterized by nuclear alterations, increased Bax expression, and reduced Bcl-2 level. Furthermore, mitochondrial permeability was up-regulated by Zol independently of p53 in association with the translocation of apoptosis-inducing factor (AIF) and endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization and cell junctions and inhibited cell migration and phosphorylation of focal adhesion kinases. The main difficulty encountered in treating cancer relates to mutations in key genes such as p53, Rb, or proteins affecting caspase signaling carried by many tumor cells. We have demonstrated for the first time that zoledronic acid activated the DNA damage S-phase checkpoint and the mitochondrial pathway via AIF and EndoG translocation, and it inhibited cell proliferation and induced cell death, bypassing these potentials mutations. Therefore, zoledronic acid may be considered as an effective therapeutic agent in clinical trials of osteosarcoma in which mutation for p53 and Rb very often occur, and where current treatment with traditional chemotherapeutic agents is ineffective.
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PMID:Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status. 1705 Aug 6

Since osteosarcoma is a drug-resistant disease, the aim of the present study was to explore the possible interest of therapeutic approaches including nitrogen-containing biphosphonate zoledronic acid using osteosarcoma cell lines with different genetic backgrounds. Parental p53+/pRb+ U2-OS, p53-mutant U2-OS (U2-OS/175) and p53-/pRb- SAOS were sensitive to zoledronic acid with no significant differences in IC50 values. Analysis of cell cycle distribution revealed a time-dependent shifting of U2-OS cells towards G2 phase with cell cycle arrest in G2 phase at 96 h of exposure to the compound. Conversely, U2-OS/175 and SAOS cells responded to treatment with transient cell accumulation in S phase up to 48-72 h, respectively. Cell lines were exposed to increasing concentrations of cisplatin alone or combined with sub-toxic doses of zoledronic acid. A growth inhibitory effect was seen after combined treatment in U2-OS, otherwise resistant to cisplatin up to 100 ng/ml. Zoledronic acid did not efficiently sensitized U2-OS/175 and SAOS to cisplatin, thereby suggesting that different behavior may depend on p53 mutation. This data was confirmed in U2-OS cells where p53 expression was downregulated by RNA interference. Present findings indicate occurrence of sensitization to cisplatin by zoledronic acid in wild-type p53 osteosarcoma cells but not in p53-null cells nor in cells expressing a dominant-negative form of p53, supporting that wild-type p53 is required for synergistic interaction of cisplatin and zoledronic acid.
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PMID:Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells. 1711 7


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