Proliferation is necessary for both repair and mutation in transgenic mouse cells

Bielas, Jason H.; Heddle, John A.

doi:10.1073/pnas.190330997

Cited by 108 publications

(75 citation statements)

References 18 publications

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“…This conclusion is in agreement with an evidence that proliferation is necessary for both repair and mutation in cells [34]. Obviously, there are no common patterns of age related changes in DNA synthesis and repair or in proliferative activity of different tissues with age [8,13].…”

Section: Is the Susceptibility To Carcinogenesis Similar In Differentsupporting

confidence: 89%

The relationship between aging and carcinogenesis: a critical appraisal

Anisimov

2003

Critical Reviews in Oncology/Hematology

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The incidence of cancer increases with age in humans and in laboratory animals alike. There are different patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by several mechanisms: (1) tissue accumulation of cells in late stages of carcinogenesis; (2) alterations in homeostasis, in particular, alterations in immune and endocrine system and (3) telomere instability linking aging and increased cancer risk. Increased susceptibility to the effects of tumor promoters is found both in aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Available evidence supporting the relevance of replicative senescence of human cells and telomere biology to human cancer seems quite strong, however, the evidence linking cellular senescence to human aging is controversial and required additional stuidies. Data on the acceleration of aging by carcinogenic agents as well as on increased cancer risk in patients with

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Section: Is the Susceptibility To Carcinogenesis Similar In Differentsupporting

confidence: 89%

The relationship between aging and carcinogenesis: a critical appraisal

Anisimov

2003

Critical Reviews in Oncology/Hematology

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“…1C). DNA breaks in proliferating cells lead to accumulation of mutations and apoptosis (15,22), but we find no evidence of apoptosis. The cells appear normal (Fig.…”

Section: Resultscontrasting

confidence: 57%

Cells adapted to high NaCl have many DNA breaks and impaired DNA repair both in cell culture and in vivo

Dmitrieva

Cai

Burg

2004

Proc. Natl. Acad. Sci. U.S.A.

109

139

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Acute exposure of cells in culture to high NaCl damages DNA and impairs its repair. However, after several hours of cell cycle arrest, cells multiply in the hypertonic medium. Here, we show that, although adapted cells proliferate rapidly and do not become apoptotic, they nevertheless contain numerous DNA breaks, which do not elicit a DNA damage response. Thus, in adapted cells, Mre11 exonuclease is mainly present in the cytoplasm, rather than nucleus, and histone H2AX and chk1 are not phosphorylated, as they normally would be in response to DNA damage. Also, the adapted cells are deficient in repair of luciferase reporter plasmids damaged by UV irradiation. On the other hand, the DNA damage response activates rapidly when the level of NaCl is reduced. Then, Mre11 moves into the nucleus, and H2AX and chk1 become phosphorylated. Renal inner medullary cells in vivo are normally exposed to a variable, but always high, level of NaCl. As with adapted cells in culture, inner medullary cells in normal mice exhibit numerous DNA breaks. These DNA breaks are rapidly repaired when the NaCl level is decreased by injection of the diuretic furosemide. Moreover, repair of DNA breaks induced by ionizing radiation is inhibited in the inner medulla. Histone H2AX does not become phosphorylated, and repair synthesis is not detectable in response to total body irradiation unless NaCl is lowered by furosemide. Thus, both in cell culture and in vivo, although cells adapt to high NaCl, their DNA is damaged and its repair is inhibited.

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“…By contrast, the key function of cycling cells is to perform DNA replication and cell division. Because their chromatin structure is open and DNA is vulnerable to damage by oxidants, 70 they have developed an endogenous mechanism to control the expression of proinflammatory and oxidative genes so that DNA damage may be prevented. COX-2 may be considered as a prototype of the proinflammatory genes that impose threat to DNA integrity when they are overexpressed.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Control of COX-2 via C/EBPβ

Wu¹,

Liou²,

Cieslik³

2005

ATVB

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Abstract-Cyclooxygenase-2 (COX-2) is a highly inducible enzyme exerting diverse actions on cell functions, including proliferation, migration, and DNA damage. Enhanced COX-2 expression may be protective, but excessive expression may be harmful, causing inflammation, atheromatous plaque instability, and intimal hyperplasia. COX-2 transcriptional activation by proinflammatory mediators has been extensively characterized. In this review, the role of C/EBP in regulating COX-2 transcription is highlighted. Recent advances in control of COX-2 transcription by aspirin and salicylate and by a cell cycle-dependent endogenous mechanism are described. The recent progress sheds light on the pathophysiological mechanisms of COX-2 and new transcription-based strategy for controlling COX-2 overexpression and COX-2-mediated cardiovascular diseases. Key Words: aspirin Ⅲ C/EBP Ⅲ COX-2 Ⅲ inflammation Ⅲ NF-B C yclooxygenase (COX, also known as prostaglandin [PG] H synthase or PGHS) occupies a pivotal position in PG and thromboxane A 2 (TXA 2 ) synthesis. It is a bifunctional enzyme containing a cyclooxygenase catalytic center, which adds 2 oxygen (bisoxygenation) to arachidonic acid (AA) to form a peroxide, PGG 2 , and a peroxidase active site, which reduces PGG 2 to PGH 2 . 1 PGH 2 is a common precursor for synthesis of biologically active prostanoids, including PGE 2 , PGI 2 (prostacyclin), TXA 2 , PGD 2 , and PGF 2␣ . There are 2 isoforms of COX; COX-1 is constitutively expressed, whereas COX-2 is inducible by diverse cytokines, mitogenic factors, and endotoxins. 2 These 2 isoforms of COX share a high degree of sequence identity and structural resemblance. 1 Both are homodimers with a long substrate channel and a stretch of hydrophobic residues that anchor the enzymes to the inner surface of endoplasmic reticulum and nuclear envelope. 3 Both enzymes contain heme with almost identical spectral characteristics and comparable catalytic parameters. 1 Thus, these 2 enzymes catalyze the generation of a similar profile of AA metabolites and might seem to have overlapped cellular activities. However, results from recent studies have provided unequivocal evidence for distinct cellular activities and different pathophysiological roles between these 2 enzymes. COX-2 has been implicated in diverse physiological and pathophysiological processes from renal and cardiovascular physiology to inflammation and tumorigenesis. 4 -9 In this review, we concentrate on its roles in cardiovascular diseases, with a focus on novel aspects of its transcriptional activation by proinflammatory mediators and the control of its transcriptional activation by aspirin and an endogenous mechanism. COX-2 Overexpression and Cardiovascular DiseasesUnder physiological conditions, COX-2 expression in vascular and cardiac endothelial cells is stimulated primarily by physical forces such as shear stress. 10,11 On endothelial activation, cytosolic phospholipase A 2 is translocated and colocalized with COX-2 and prostacyclin (PGI 2 ) synthase to endoplasmic reticulum and...

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Proliferation is necessary for both repair and mutation in transgenic mouse cells

Cited by 108 publications

References 18 publications

The relationship between aging and carcinogenesis: a critical appraisal

The relationship between aging and carcinogenesis: a critical appraisal

Cells adapted to high NaCl have many DNA breaks and impaired DNA repair both in cell culture and in vivo

Transcriptional Control of COX-2 via C/EBPβ

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