Parkinson's disease and Alzheimer's disease: hypersensitivity to X rays in cultured cell lines.

Robbins, Jay H.; Otsuka, Fujio; Tarone, Robert E.; Polinsky, R. J.; Brumback, R. A.; Nee, Linda E.

doi:10.1136/jnnp.48.9.916

Cited by 101 publications

(33 citation statements)

References 30 publications

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“…In contrast to the limited differences between normal and AT cells at the same dose, induction of gadd45 mRNA was clearly greater in normal cells at equitoxic X-ray doses. In both lymphoblasts (27) and fibroblasts (31), an approximately 2.5-fold-lower dose of X rays produces the same level of cell lethality in AT cells as in normal cells. Cell survival for AT cells at 2 Gy was equivalent to that produced in normal cells by 5 Gy.…”

Section: Resultsmentioning

confidence: 99%

Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.

Papathanasiou¹,

Kerr²,

Robbins³

et al. 1991

Mol. Cell. Biol.

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244

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The effect of ionizing radiation on the expression of two DNA-damage-inducible genes, designated gadd45 and gaddl53, was examined in cultured human cells. These genes have previously been shown to be strongly and coordinately induced by UV radiation and alkylating agents in human and hamster cells. We found that the gadd45 but not the gaddl53 gene is strongly induced by X rays in human cells. The level of gadd45 mRNA increased rapidly after X rays at doses as low as 2 Gy. After 20 Gy of X rays, gadd45 induction, as measured by increased amounts of mRNA, was similar to that produced by the most effective dose of the alkylating agent methyl methanesulfonate. No induction was seen after treatment of either human or hamster cells with 12-O-tetradecanoylphorbol-13-acetate, a known activator of protein kinase C (PKC). Therefore, gadd45 represents the only known mammalian X-ray-responsive gene whose induction is not mediated by PKC. However, induction was blocked by the protein kinase inhibitor H7, indicating that induction is mediated by some other kinase(s). Sequence analysis of human and hamster cDNA clones demonstrated that this gene has been highly conserved and encodes a novel 165-amino-acid polypeptide which is 96% identical in the two species. This gene was localized to the short arm of human chromosome 1 between p12 and p34. When induction in lymphoblast lines from four normal individuals was compared with that in lines from four patients with ataxia telangiectasia, induction by X rays ofgadd45 mRNA was less in the cell lines from this cancer-prone radiosensitive disorder. Our results provide evidence for the existence of an X-ray stress response in human cells which is independent of PKC and which is abnormal in ataxia telangiectasia.There is increasing evidence that ionizing radiation can induce specific genes in mammalian and other eucaryotic cells. Such genes may have functions like those in procaryotes, in which genes encoding protective functions, such as DNA repair processes, can be induced (39). Prior treatment with a low dose of X rays induces a transient (usually small) protection, manifested as an increased survival or as a reduction in chromosomal damage, against a second, higher dose in human lymphocytes (25), Chinese hamster cells (12), and insect cells (15). These protective effects are blocked by inhibitors of protein (12) and RNA synthesis (15), indicating that such processes may be mediated by the induction of particular genes. The finding that certain proteins increase in abundance after X irradiation of human cells also provides evidence for X-ray-inducible genes (2). Recently, tumor necrosis factor a (TNF) mRNA has been reported to increase in human sarcoma cells after ionizing radiation (9). TNF has a role in a variety of cellular processes, including the acute-phase response and inflammation (1), and thus its induction probably represents a general response to cell injury rather than a specific response to X rays or other DNA-damaging agents. Transcription from the long terminal repeat o...

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Section: Resultsmentioning

confidence: 99%

Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.

Papathanasiou¹,

Kerr²,

Robbins³

et al. 1991

Mol. Cell. Biol.

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244

120

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“…AD (8) and DS (9) cells have normal survival after exposure to 254-nm UV radiation. AD cells have normal UV-induced unscheduled DNA synthesis in the genome overall (10) and normal removal of UVinduced pyrimidine dimers from transcribing genes (11).…”

mentioning

confidence: 99%

“…AD cells have normal UV-induced unscheduled DNA synthesis in the genome overall (10) and normal removal of UVinduced pyrimidine dimers from transcribing genes (11). But AD and DS cells respond abnormally to the ionizing radiationtype of DNA damage in cell-survival (8,(10)(11)(12), chromatidaberration (13)(14)(15), and alkaline-elution (10,12) assays that are dependent on DNA repair (1,8,(10)(11)(12)(13)(14)(15). However, these assays show abnormalities too small to be diagnostically useful.…”

mentioning

confidence: 99%

Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture.

Parshad¹,

Sanford²,

Price³

et al. 1996

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

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The neurodegeneration and amyloid deposition of sporadic Alzheimer disease (AD) also occur in familial AD and in all trisomy-21 Down syndrome (DS) patients, suggesting a common pathogenetic mechanism. We investigated whether defective processing of damaged DNA might be that mechanism, as postulated for the neurodegeneration in xeroderma pigmentosum, a disease with defective repair not only of UV radiation-induced, but also of some oxygen free radical-induced, DNA

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“…irradiation, elaborated the theory that DNA damage from endogenous or exogenous sources is the cause of primary degenerations of excitable tissues. He sought evidence for such a theory in several inheritable or non-inheritable degenerative diseases and reported in its support survival studies suggesting hypersensitivity to X-rays and MNNG in cell lines (usually EB virus-transformed lymphocitoid cells) derived from individuals affected by tuberous sclerosis, familial dysautonomia, Huntington disease, olivoponto cerebellar atrophy, sporadic autonomic neurodegeneration (Shy-Drayer S.), Usher syndrome, retinitis pigmentosa, Alzheimer disease, Parkinson disease, in fantile spinal muscular atrophy, myotonic muscular atrophy and Duchenne, Becker muscular dystrophy Robbins et al 1980Robbins et al , 1984Robbins et al , 1985Scudiero etal. 1981Scudiero etal.…”

Section: Searches For Dna Repair Defects Based On Specific Aetiopathomentioning

confidence: 99%

DNA Maintenance and its Relation to Human Pathology

Giannelli

1986

Journal of Cell Science

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Parkinson's disease and Alzheimer's disease: hypersensitivity to X rays in cultured cell lines.

Cited by 101 publications

References 30 publications

Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.

Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.

Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture.

DNA Maintenance and its Relation to Human Pathology

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