Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two systems are essential in humans for genome integrity, DNA repair and apoptosis. Cells that are defective in DNA repair tend to accumulate excess DNA damage. Cells defective in apoptosis tend to survive with excess DNA damage and thus allow DNA replication past DNA damages, causing mutations leading to carcinogenesis. It has recently become apparent that key proteins which contribute to cellular survival by acting in DNA repair become executioners in the face of excess DNA damage. Five major DNA repair pathways are homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR). In each of these DNA repair pathways, key proteins occur with dual functions in DNA damage sensing/repair and apoptosis. Proteins with these dual roles occur in: (1) HRR (BRCA1, ATM, ATR, WRN, BLM, Tip60 and p53); (2) NHEJ (the catalytic subunit of DNA-PK); (3) NER (XPB, XPD, p53 and p33(ING1b)); (4) BER (Ref-1/Ape, poly(ADP-ribose) polymerase-1 (PARP-1) and p53); (5) MMR (MSH2, MSH6, MLH1 and PMS2). For a number of these dual-role proteins, germ line mutations causing them to be defective also predispose individuals to cancer. Such proteins include BRCA1, ATM, WRN, BLM, p53, XPB, XPD, MSH2, MSH6, MLH1 and PMS2.
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PMID:DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. 1205 32

Poly(ADP-ribose) and poly(ADP-ribose) polymerase (PARP) were discovered about 40 years ago, but their significance was not well elucidated until recently. In the early stage of the history of PARP, the presence of antibodies in the sera of human patients with lupus erythematosus indicated its natural occurrence. PARP, as well as the degrading enzyme, poly(ADP-ribose) glycohydrolase (PARG), are present in most eukaryotes except for yeasts. Studies that used inhibitors of PARP indicated the involvement of PARP and poly(ADP-ribose) in DNA damage repair, and eventually PARP was purified and the gene was cloned. Molecular analysis then revealed various functional domains, such as the one for binding to strand breaks of DNA. Parp-1-deficient and Parg-deficient cells showed, in general, enhanced sensitivity to the lethal effects of ionizing radiation and alkylating agents. Parp-1 knockout mouse embryonic stem cells developed into teratocarcinoma-like tumors when injected subcutaneously into nude mice, these tumors featuring giant cells similar to syncytiotrophoblastic giant cells with hyperploidy. Parp-1 was also found in centrosomes, suggesting that poly(ADP-ribose) and PARP-1 are functionally involved in the maintenance of chromatin structure and the equal distribution of chromosomes into daughter cells. Intriguing findings on the real biological significance continue to be generated, with new light shed on mechanisms of carcinogenesis and pointing to novel cancer treatments. Highlights during the last four decades of studies by laboratories focusing on poly(ADP-ribose)/PARP, including our own, are condensed and summarized in this review.
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PMID:Poly(ADP-ribose) and carcinogenesis. 1456 54

Endometrial carcinomas are the most common malignancy of the female genital tract. Although the downregulation of the progesterone receptor (PR) in the progression of endometrioid carcinomas (ECs) has been well documented, the mechanism of PR alteration in endometrioid carcinogenesis is poorly understood. Recently, biochemical studies have shown that the DNA strand break-sensing molecule poly(ADP-ribose) polymerase (PARP-1) was associated with the DNA binding domain of PR. In our present study, we show that in normal endometrial epithelium, the expression level of PARP-1 protein is high in the proliferative phase but markedly decreases during the secretory phase. Interestingly, PARP-1 expression gradually increases in nonatypical and atypical endometrial hyperplasia, reaching its highest level in grade I, and decreases significantly toward grade III ECs. Notably, PARP-1 and PR expressions, in each stage, are positively correlated (p < 0.0001), with the exception of nonendometrioid carcinomas. Thus, these data suggest that PARP-1 is substantially involved in the regulation of progesterone action in the development of ECs.
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PMID:Poly(ADP-ribose) polymerase-1, a novel partner of progesterone receptors in endometrial cancer and its precursors. 1496 67

Poly (ADP-ribose) polymerase-1 (PARP-1)-deficient mice are protected against septic shock, type I diabetes, stroke and inflammation. It is now accepted that inflammation and related events, such as activation of NF-kappaB, are key components in the initiation and progression of epithelial cancer and in particular in the neoplastic transformation of keratinocytes and skin carcinogenesis. Here, we report that PARP-1-deficient mice display a strikingly reduced susceptibility to skin carcinogenesis. In parp-1(-/-) mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumor-bearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1(-/-) mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-kappaB is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-kappaB activation and induction kappaB-target genes did not take place during the promotion of tumor development. These results suggest that PARP-1 abolition impairs the promotion of skin carcinogenesis interfering with the activation of NF-kappaB and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.
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PMID:Crosstalk between PARP-1 and NF-kappaB modulates the promotion of skin neoplasia. 1507 72

Poly(ADP-ribosyl)ation is a DNA strand break-driven post-translational modification of proteins catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), with NAD+ serving as substrate. Poly(ADP-ribosyl)ation is triggered by DNA strand breaks, is functionally associated with DNA repair pathways and is a survival factor for cells under low to moderate levels of genotoxic stress. We have previously described a positive correlation between poly(ADP-ribosyl)ation capacity of mononuclear blood cells with longevity of mammalian species. Our comparison of purified recombinant human and rat PARP-1 revealed that this correlation might be explained in part by evolutionary sequence divergence. We have also developed molecular genetic approaches to modulate the poly(ADP-ribosyl)ation status in living cells. Our results revealed that PARP-1 acts as a negative regulator of DNA damage-induced genomic instability, the latter being known as an important driving force for carcinogenesis. Our recent data obtained in transgenic mice with selective expression of a dominant negative version of PARP-1 in basal skin keratinocytes indicate that PARP-1 activity suppresses skin papilloma formation in a two-stage skin carcinogenesis protocol. It is tempting to speculate that increased poly(ADP-ribosyl)ation capacity in long-lived species might help retard the accumulation of DNA damage and of mutations and thus slow down the rate of aging and of carcinogenesis more efficiently as compared with short-lived animals.
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PMID:Poly(ADP-ribosyl)ation and aging. 1558 75

In the present paper, the involvement of the family of poly(ADP-ribose) polymerases (PARPs), and especially of PARP-1, in mammalian longevity is reviewed. PARPs catalyse poly(ADP-ribosyl)ation, a covalent post-translational protein modification in eukaryotic cells. PARP-1 and PARP-2 are activated by DNA strand breaks, play a role in DNA base-excision repair (BER) and are survival factors for cells exposed to low doses of ionising radiation or alkylating agents. PARP-1 is the main catalyst of poly(ADP-ribosyl)ation in living cells under conditions of DNA breakage, accounting for about 90% of cellular poly(ADP-ribose). DNA-damage-induced poly(ADP-ribosyl)ation also functions as a negative regulator of DNA damage-induced genomic instability. Cellular poly(ADP-ribosyl)ation capacity in permeabilised mononuclear blood cells (MNC) is positively correlated with life span of mammalian species. Furthermore PARP-1 physically interacts with WRN, the protein deficient in Werner syndrome, a human progeroid disorder, and PARP-1 and WRN functionally cooperate in preventing carcinogenesis in vivo. Some of the other members of the PARP family have also been revealed as important regulators of cellular functions relating to ageing/longevity. In particular, tankyrase-1, tankyrase-2, PARP-2 as well as PARP-1 have been found in association with telomeric DNA and are able to poly(ADP-ribosyl)ate the telomere-binding proteins TRF-1 and TRF-2, thus blocking their DNA-binding activity and controlling telomere extension by telomerase.
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PMID:The emerging role of poly(ADP-ribose) polymerase-1 in longevity. 1574 77

PARP-1 [poly(ADP-ribose) polymerase-1) is a nuclear enzyme that is involved in several cellular functions, including DNA repair, DNA transcription, carcinogenesis and apoptosis. The activity directed by the PARP-1 gene promoter is mainly dictated through its recognition by the transcription factors Sp1 and Sp3 (where Sp is specificity protein). In the present study, we investigated whether (i) both PARP-1 expression and PARP-1 enzymatic activity are under the influence of cell density in primary cultured cells, and (ii) whether its pattern of expression is co-ordinated with that of Sp1/Sp3 at varying cell densities and upon cell passages. All types of cultured cells expressed PARP-1 in Western blot when grown to sub-confluence. However, a dramatic reduction was observed at post-confluence. Similarly, high levels of Sp1/Sp3 were observed by both Western blot and EMSAs (electrophoretic mobility-shift assays) in sub-confluent,but not post-confluent, cells. Consistent with these results, the promoter of the rPARP-1 (rat PARP-1) gene directed high levels of activity in sub-confluent, but not confluent, cells upon transfection of various CAT (chloramphenicol acetyltransferase)-rPARP-1 promoter constructs into cultured cells. The positive regulatory influence of Sp1 was not solely exerted on the rPARP-1 promoter constructs, as inhibition of endogenous Sp1 expression in HDKs(human dermal keratinocytes) through the transfection of Sp1 RNAi (RNA interference) considerably reduced endogenous hPARP-1 (human PARP-1) expression as well. The reduction in PARP-1 protein expression as cells reached confluence also translated into a corresponding reduction in PARP-1 activity. In addition, expression of both Sp1/Sp3, as well as that of PARP-1,was dramatically reduced as cells were passaged in culture and progressed towards irreversible terminal differentiation. PARP-1 gene expression therefore appears to be co-ordinated with that of Sp1 and Sp3 in primary cultured cells, suggesting that PARP-1 may play some important functions during the proliferative burst that characterizes wound healing.
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PMID:Regulation of the poly(ADP-ribose) polymerase-1 gene expression by the transcription factors Sp1 and Sp3 is under the influence of cell density in primary cultured cells. 1577 84

Carcinogenesis involves multiple steps and pathways with functional alterations in a variety of genes. There is accumulating evidence that a deficiency of poly(ADP-ribose) polymerase (PARP)-1 leads to DNA repair defects, genomic instability, failure of induction of cell death and modulation of gene transcription. PARP-1 also supports the growth of tumor cells in certain situations. Genetic analyses of the PARP-1 gene have demonstrated alterations in neoplasms, and a mutation affecting the conserved amino acid E251 in germ cell tumors, as well as an association of a single-nucleotide polymorphism V762A with risk of prostate cancer. Recent development of a selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), the enzyme primarily responsible for degradation of poly(ADP-ribose), and PARG-deficient animals should facilitate studies of the relationship of poly(ADP-ribose) with carcinogenesis. Inhibitors of PARP have also suggested roles in the pathogenesis of autoimmune disease, and a promoter haplotype of PARP-1 confers a higher risk of rheumatoid arthritis. Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases. Furthermore, there is potential for sensitization to chemo- and radiation therapy of cancers as well as the treatment of autoimmune disease with development of stronger PARP inhibitors.
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PMID:Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease. 1586 2

3-nitrotyrosine (NO2-Tyr) is thought to be a specific marker of cell injury during oxidative damage. We have evaluated the role of poly(ADP-ribose)polymerase-1 (PARP-1) in protein nitration after treatment of immortalized fibroblasts parp-1+/+ and parp-1-/- with the alkylating agent 2'-methyl-2'-nitroso-urea (MNU). Both cell lines showed increased iNOS expression following MNU treatment in parallel with a selective induction of tyrosine nitration of different proteins. PARP-1 deficient cells displayed a delayed iNOS accumulation, reduced number of nitrated proteins, and a lower global nitrotyrosine "footprint." We have identified the mitochondrial compartment as the major site of oxidative stress during DNA damage, being MnSOD one of the NO2-Tyr-modified proteins, but not in parp-1-/- cells. These results suggest that NO-derived injury can be modulated by proteins involved in the response to genotoxic damage, such as PARP-1, and may account for the limited oxidative injury in parp-1 knockout mice during carcinogenesis and inflammation.
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PMID:PARP-1-dependent 3-nitrotyrosine protein modification after DNA damage. 1605 7

Poly(ADP-ribose) (PAR) and the PAR polymerases (PARPs) that catalyze its synthesis from donor nicotinamide adenine dinucleotide (NAD+) molecules have received considerable attention in the recent literature. Poly(ADP-ribosyl)ation (PARylation) plays diverse roles in many molecular and cellular processes, including DNA damage detection and repair, chromatin modification, transcription, cell death pathways, insulator function, and mitotic apparatus function. These processes are critical for many physiological and pathophysiological outcomes, including genome maintenance, carcinogenesis, aging, inflammation, and neuronal function. This review highlights recent work on the biochemistry, molecular biology, physiology, and pathophysiology of PARylation, focusing on the activity of PARP-1, the most abundantly expressed member of a family of PARP proteins. In addition, connections between nuclear NAD+ metabolism and nuclear signaling through PARP-1 are discussed.
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PMID:Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. 1614 Sep 81


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