Oxidative Modification of Proteins: Age-Related Changes

Chakravarti, Bulbul; Chakravarti, Deb N.

doi:10.1159/000097865

Cited by 154 publications

(97 citation statements)

References 233 publications

(146 reference statements)

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“…Oxidative stress is induced by a vast range of factors, including xenobiotics, drugs, heavy metals and ionizing radiation (Kaspar et al, 2009). High concentrations of ROS are hazardous for living organisms because they damage all cellular components, including DNA, lipids and proteins (Ames, 1983;Brazilai and Yamamoto, 2004;Chakravarti and Chakravarti, 2007), leading to many pathological conditions, including cancer, neurodegenerative diseases, arthritis, atherosclerosis and inflammation (Grisham and McCord, 1986;Ames et al, 1995;Ward, 1994;Breen and Murphy, 1995;Rosen et al, 1995). It is apparent that uncontrolled levels of ROS can cause a wide range of disorders.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2–Cul3–Rbx1 complex to allow normal Nrf2 activation and repression

Kaspar

Niture

Jaiswal

2012

Journal of Cell Science

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SummaryINrf2 (Keap1) serves as a negative regulator of the cytoprotective transcription factor Nrf2. At basal levels, INrf2 functions as a substrate adaptor to sequester Nrf2 into the Cul3-Rbx1 E3 ligase complex for ubiquitylation and proteasomal degradation. In response to antioxidants, Nrf2 is released from the INrf2-Cul3-Rbx1 complex and translocates into the nucleus, where it activates ARE-mediated cytoprotective gene expression. The present studies demonstrate that INrf2, Cul3 and Rbx1 export out of the nucleus and are degraded during the early or pre-induction response to antioxidants. Mutation of Tyr85 in INrf2 stymied the nuclear export of INrf2, suggesting that tyrosine phosphorylation controls the pre-induction nuclear export and degradation in response to antioxidants. The nuclear export of Cul3-Rbx1 were also blocked when INrf2Tyr85 was mutated, suggesting that INrf2-Cul3-Rbx1 undergo nuclear export as a complex. INrf2 siRNA also inhibited the nuclear export of Cul3-Rbx1, confirming that Cul3-Rbx1 requires INrf2 for nuclear export. Newly synthesized INrf2-Cul3-Rbx1 is imported back into the nucleus during the post-induction period to ubiquitylate and degrade Nrf2. Mutation of INrf2Tyr85 had no effect on activation of Nrf2 but led to nuclear accumulation of Nrf2 during the post-induction period owing to reduced export and degradation of Nrf2. Our results also showed that nuclear export and degradation followed by the new synthesis of INrf2-Cul3-Rbx1 controls the cellular abundance of the proteins during different phases of antioxidant responses. In conclusion, the early or pre-induction nuclear export of INrf2 in response to antioxidants is controlled by tyrosine phosphorylation, whereas the nuclear export of Cul3 and Rbx1 is controlled by INrf2, allowing normal activation or repression of Nrf2.

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Section: Introductionmentioning

confidence: 99%

Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2–Cul3–Rbx1 complex to allow normal Nrf2 activation and repression

Kaspar

Niture

Jaiswal

2012

Journal of Cell Science

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“…Reactive oxygen species (ROS) (Chakravarti and Chakravarti 2007), which are generated either as products of normal metabolism (Haenold et al 2005) or by interaction with environmental factors such as UV radiation (Yaar and Gilchrest 2007), are the primary agents of protein oxidation. The influence of ROS on cellular metabolism has been the subject of intense study and it has become evident that cellmediated perturbations in elastic fibre homeostasis, as a result of ROS-induced tropoelastin and MMP transcription (Wlaschek et al 2001), contribute to tissue ageing.…”

Section: Degradationmentioning

confidence: 99%

Tissue elasticity and the ageing elastic fibre

Sherratt

2009

AGE

265

189

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The ability of elastic tissues to deform under physiological forces and to subsequently release stored energy to drive passive recoil is vital to the function of many dynamic tissues. Within vertebrates, elastic fibres allow arteries and lungs to expand and contract, thus controlling variations in blood pressure and returning the pulmonary system to a resting state. Elastic fibres are composite structures composed of a cross-linked elastin core and an outer layer of fibrillin microfibrils. These two components perform distinct roles; elastin stores energy and drives passive recoil, whilst fibrillin microfibrils direct elastogenesis, mediate cell signalling, maintain tissue homeostasis via TGFβ sequestration and potentially act to reinforce the elastic fibre. In many tissues reduced elasticity, as a result of compromised elastic fibre function, becomes increasingly prevalent with age and contributes significantly to the burden of human morbidity and mortality. This review considers how the unique molecular structure, tissue distribution and longevity of elastic fibres pre-disposes these abundant extracellular matrix structures to the accumulation of damage in ageing dermal, pulmonary and vascular tissues. As compromised elasticity is a common feature of ageing dynamic tissues, the development of strategies to prevent, limit or reverse this loss of function will play a key role in reducing age-related morbidity and mortality.

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“…Free radicals are produced in excess during mitochondrial respiration and can react with biomolecules, altering their functions 2,6 . This molecular damage can be minor in healthy subjects because the free radicals can be trapped or neutralized by the subject's natural antioxidant systems 1,3,4 .…”

Section: Discussionmentioning

confidence: 99%

“…The human body has several enzymes that chemically decompose H 2 O 2 , including catalase, peroxidases, and peroxiredoxins 3 . Lipid peroxidation of cell membranes, which produces malondialdehyde (MDA), is considered a good indicator of oxidative stress 6 . The antioxidant power capacity of a system is measured by the antioxidant capacity of plasma systems to inhibit 50% of the formation of thiobarbituric acid reactive substances (TBARS) 3,4,6 .…”

Section: Introductionmentioning

confidence: 99%