Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury
Aging is generally accompanied by reduced tolerance to oxidative stress and altered responsiveness to proliferative signals. We have shown that hepatocytes derived from aged rats (24-26 months) exhibit greater sensitivity to H(2)O(2) treatment and reduced proliferation following epidermal growth fac...
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Veröffentlicht in: | The Journal of biological chemistry 2003-05, Vol.278 (19), p.16726-16731 |
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container_title | The Journal of biological chemistry |
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creator | Ikeyama, Shizuo Wang, Xian-Tao Li, Ji Podlutsky, Andrej Martindale, Jennifer L Kokkonen, Gertrude van Huizen, Rika Gorospe, Myriam Holbrook, Nikki J |
description | Aging is generally accompanied by reduced tolerance to oxidative stress and altered responsiveness to proliferative signals. We have shown that hepatocytes derived from aged rats (24-26 months) exhibit greater sensitivity to H(2)O(2) treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5-6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H(2)O(2) treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. This effect was absent in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H(2)O(2) treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress. Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H(2)O(2). We propose a model whereby the diminished ability of old hepatocytes to overcome an EGF-triggered reactive oxygen species load leads to induction of the proapoptotic gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our findings point to gadd153 expression levels as an important factor in liver aging. |
doi_str_mv | 10.1074/jbc.M300677200 |
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We have shown that hepatocytes derived from aged rats (24-26 months) exhibit greater sensitivity to H(2)O(2) treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5-6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H(2)O(2) treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. This effect was absent in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H(2)O(2) treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress. Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H(2)O(2). We propose a model whereby the diminished ability of old hepatocytes to overcome an EGF-triggered reactive oxygen species load leads to induction of the proapoptotic gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our findings point to gadd153 expression levels as an important factor in liver aging.</description><identifier>ISSN: 0021-9258</identifier><identifier>DOI: 10.1074/jbc.M300677200</identifier><identifier>PMID: 12609979</identifier><language>eng</language><publisher>United States</publisher><subject>Aging - genetics ; Aging - metabolism ; Aging - pathology ; Animals ; Apoptosis - genetics ; CCAAT-Enhancer-Binding Proteins - biosynthesis ; CCAAT-Enhancer-Binding Proteins - genetics ; Gene Expression Regulation ; Liver - metabolism ; Liver - pathology ; Male ; Oxidative Stress - genetics ; Rats ; Rats, Inbred F344 ; Transcription Factor CHOP ; Transcription Factors - biosynthesis ; Transcription Factors - genetics</subject><ispartof>The Journal of biological chemistry, 2003-05, Vol.278 (19), p.16726-16731</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12609979$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ikeyama, Shizuo</creatorcontrib><creatorcontrib>Wang, Xian-Tao</creatorcontrib><creatorcontrib>Li, Ji</creatorcontrib><creatorcontrib>Podlutsky, Andrej</creatorcontrib><creatorcontrib>Martindale, Jennifer L</creatorcontrib><creatorcontrib>Kokkonen, Gertrude</creatorcontrib><creatorcontrib>van Huizen, Rika</creatorcontrib><creatorcontrib>Gorospe, Myriam</creatorcontrib><creatorcontrib>Holbrook, Nikki J</creatorcontrib><title>Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Aging is generally accompanied by reduced tolerance to oxidative stress and altered responsiveness to proliferative signals. We have shown that hepatocytes derived from aged rats (24-26 months) exhibit greater sensitivity to H(2)O(2) treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5-6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H(2)O(2) treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. This effect was absent in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H(2)O(2) treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress. Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H(2)O(2). We propose a model whereby the diminished ability of old hepatocytes to overcome an EGF-triggered reactive oxygen species load leads to induction of the proapoptotic gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our findings point to gadd153 expression levels as an important factor in liver aging.</description><subject>Aging - genetics</subject><subject>Aging - metabolism</subject><subject>Aging - pathology</subject><subject>Animals</subject><subject>Apoptosis - genetics</subject><subject>CCAAT-Enhancer-Binding Proteins - biosynthesis</subject><subject>CCAAT-Enhancer-Binding Proteins - genetics</subject><subject>Gene Expression Regulation</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Male</subject><subject>Oxidative Stress - genetics</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Transcription Factor CHOP</subject><subject>Transcription Factors - biosynthesis</subject><subject>Transcription Factors - genetics</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkL1PwzAQxT2AaCmsjMgTW1p_JLE9ooovqYgF5sixL6mr1A6xW1r-elpRZm456fR7p_ceQjeUTCkR-WxVm-krJ6QUghFyhsaEMJopVsgRuoxxRQ6TK3qBRpSVRCmhxmj3sOsHiNEFj0OD0xJwP4RM96FPITmDW_CAW20tLfjMLEOPXcTQwVYnsNh53LktDPjLpSXWrfMt1t7iCD665L4hYgNdF3EKOOyc1T4dNKvNsL9C543uIlyf9gR9PD68z5-zxdvTy_x-kfWMy5RRo4jirBSWWCAl4_nxUNREUyMkV0KKJm8IE1opKeuiYLouQIHRvGG1qfkE3f3-PcT63EBM1drFoyftIWxiJTjLc67kvyCVIue8OIK3J3BTr8FW_eDWethXf6XyH69zeCU</recordid><startdate>20030509</startdate><enddate>20030509</enddate><creator>Ikeyama, Shizuo</creator><creator>Wang, Xian-Tao</creator><creator>Li, Ji</creator><creator>Podlutsky, Andrej</creator><creator>Martindale, Jennifer L</creator><creator>Kokkonen, Gertrude</creator><creator>van Huizen, Rika</creator><creator>Gorospe, Myriam</creator><creator>Holbrook, Nikki J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20030509</creationdate><title>Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury</title><author>Ikeyama, Shizuo ; 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We have shown that hepatocytes derived from aged rats (24-26 months) exhibit greater sensitivity to H(2)O(2) treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5-6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H(2)O(2) treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. 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subjects | Aging - genetics Aging - metabolism Aging - pathology Animals Apoptosis - genetics CCAAT-Enhancer-Binding Proteins - biosynthesis CCAAT-Enhancer-Binding Proteins - genetics Gene Expression Regulation Liver - metabolism Liver - pathology Male Oxidative Stress - genetics Rats Rats, Inbred F344 Transcription Factor CHOP Transcription Factors - biosynthesis Transcription Factors - genetics |
title | Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury |
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