Age-related accumulation of oxidative DNA damage and alterations in levels of p16INK4a/CDKN2a, p21WAF1/CIP1/SDI1 and p27KIP1 in human CD4+ T cell clones in vitro

Hyland, Paul; Barnett, Christopher R.; Pawelec, Graham; Barnett, Yvonne

doi:10.1016/s0047-6374(01)00254-8

Cited by 43 publications

(22 citation statements)

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“…The results of our investigations have demonstrated that for TCCs grown in air, an accumulation of oxidative DNA damage occurs during the replicative lifespan vitro, with a sharp rise in damage levels just ahead of the self-deletion of these clones via apoptosis (Hyland et al 2001). Alongside of this increase in levels of DNA damage we also discovered that DNA excision repair capacity declined with increasing in vitro age in TCCs from younger subjects.…”

Section: Telomere Lengths Dna Damage Levels Mitochondrialsupporting

confidence: 50%

“…6.3.3). Nonetheless, there were no consistent changes in the expression of cyclin-dependent kinase inhibitors (CKI) p16, p21 or p27, often associated (in fibroblasts) with a replicative senescent state (Hyland et al 2001). Thus, at the end of their lifespans, these TCC did not have a CKI phenotype characteristic of senescent fibroblasts (i.e.…”

Section: Culturing At Lower Oxygen Levels and Use Of Anti-oxidantsmentioning

confidence: 96%

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Ageing and Senescence in Immune Cells In Vitro and In Vivo

Pawelec

Barnett

2016

Cellular Ageing and Replicative Senescence

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Since the discovery of T cell growth factor, now known as interleukin 2 (IL 2), it has been possible to serially culture normal human T lymphocytes, something that cannot be done with other immune cells such as B cells or monocytes/macrophages. This chapter will focus on cloning efficiencies of T cells from younger or older subjects, their longevity in culture under different conditions and the progressive changes occurring over their in vitro lifespan.

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Section: Telomere Lengths Dna Damage Levels Mitochondrialsupporting

confidence: 50%

Section: Culturing At Lower Oxygen Levels and Use Of Anti-oxidantsmentioning

confidence: 96%

Ageing and Senescence in Immune Cells In Vitro and In Vivo

Pawelec

Barnett

2016

Cellular Ageing and Replicative Senescence

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“…Clones were obtained as previously described 15,16 and analyzed at different times after in vitro culture, expressed as population doublings (PD), as defined by Hyland et al 17 Fifteen CD4 ϩ T cell clones derived from peripheral blood lymphocytes from differently aged donors (Table 1) were chosen for protein analysis among those previously characterized for MSI and mRNA expression of MMR genes. 8,10 According to MSI analysis, clones were divided into stable (S) clones (those that never manifested MSI during culture) and unstable (U) clones (those presenting MSI at one or more of five analyzed loci during in vitro culture).…”

Section: Cells and Clonesmentioning

confidence: 99%

Altered Expression of Mismatch Repair Proteins Associated with Acquisition of Microsatellite Instability in a Clonal Model of Human T Lymphocyte Aging

Neri¹,

Pawelec

Facchini

et al. 2008

Rejuvenation Research

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The DNA mismatch repair system, the main postreplicative correction pathway in eukaryotic cells, has been shown to be involved in the acquisition of genetic damage during the aging of normal somatic cells, including those of the immune system. Previously, we showed that some but not all human T cell clones (TCC) in an in vitro culture aging model develop microsatellite instability (MSI), which is associated with altered expression of mismatch repair genes. Here, we analyzed levels of mismatch repair proteins as well as the corresponding mRNAs and related this to the development of microsatellite instability in TCC. Msh2, Msh3, Msh6, Pms1, and Pms2 protein expression was quantified by Western blotting. We found that clones not manifesting microsatellite instability in this in vitro model of T cell replicative aging, induced by persistent antigenic stimulation, maintain normal transcriptional control and coordination among the mismatch repair system genes, while clones which do manifest MSI display a general deregulation of gene expression, which is likely to contribute to its occurrence.

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“…It was of interest to us that the majority of these genes have products that are redox sensitive or regulated under conditions of oxidative stress. [28][29][30][31][32][33][34][35] Several of these genes for example, EGF, TGFb, catenin and ras have been implicated in the development of prostate cancer. 36 On the bases of this ''fingerprint'' analysis, Figure 6b illustrates the expression profile of genes that we selected for verification of expression by semiquantitative reverse transcriptase-PCR.…”

Section: Effect Of Organoselenium Compounds On Gene Profilesmentioning

confidence: 99%

Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells

Pinto

Sinha

Papp

et al. 2007

Intl Journal of Cancer

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Epidemiological studies and clinical trials show that selenium supplementation results in reduction of prostate cancer incidence; however, the form of selenium and mechanisms underlying protection remain largely unknown. Toward this end, we compared the effects of naturally occurring selenomethionine (SM) and Semethylselenocysteine (MSC) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) and p-xylylbis(methylselenide) p-XMS) organoselenium compounds in androgen responsive (AR) LNCaP and its androgen independent clone (AI) LNCaP C4-2 human prostate carcinoma cells on cell growth, secretion of prostate specific antigen (PSA), intracellular redox status and genomic profiles with emphasis on identifying redox sensitive genes. Both p-XSC and p-XMS reduced cell number and total protein concentration compared to control-treated AR and AI cells, while SM and MSC exhibited no effect on growth of AR and AI cells. SM, p-XSC and p-XMS but not MSC inhibited levels of secreted PSA in AR cells. SM, MSC and p-XMS increased glutathione (GSH) levels in AI LNCaP cells. By contrast, in both cell types, only p-XSC significantly decreased GSH concentrations to <50% of control suggesting either an increase in intracellular oxidative stress or a change in GSH/GSSG ratio. On the basis of RT-PCR analysis, SM and p-XSC increased p53 gene expression by 2-fold in AR cells but not in AI cells and only SM enhanced epidermal growth factor receptor in AR cells. Depending on the structure, organoselenium compounds exhibit differential effects on growth, PSA secretion, oxidative stress and selective gene responses in human prostate cancer cells and suggest the potential of developing novel organoselenium compounds as chemopreventive agents in models of human prostate cancer. ' 2006 Wiley-Liss, Inc.Key words: selenomethionine; Se-methylselenocysteine; 1,4-phenylenebis (methylene)selenocyanate; p-xylylbis(methylselenide); prostate specific antigen; prostate cancer; chemoprevention; glutathione Epidemiological studies, clinical intervention trials and preclinical models have provided evidence for a protective role of organoselenium compounds against development of human cancers, including prostate cancer. [1][2][3][4][5][6][7] Although the anticancer mechanism(s) of selenium-enriched supplements have not been clearly defined, the dramatic outcome of Clark's trial prompted additional clinical trials: Prevention of Cancer by Intervention with Selenium (PRECISE), in 3 European countries, SELECT in the United States, and the Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial. [8][9][10] On the basis of available knowledge, there are compelling viewpoints to investigate systematically how organoselenium compounds modulate the most commonly considered risk factors in the development of prostate cancer not only in cancer patients or in high risk populations but more importantly for chemopreventive measures in healthy males as intended in the SELECT trial. 11Numerous studies strongly support the feasibility of using organ...

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Age-related accumulation of oxidative DNA damage and alterations in levels of p16INK4a/CDKN2a, p21WAF1/CIP1/SDI1 and p27KIP1 in human CD4+ T cell clones in vitro

Cited by 43 publications

References 58 publications

Ageing and Senescence in Immune Cells In Vitro and In Vivo

Ageing and Senescence in Immune Cells In Vitro and In Vivo

Altered Expression of Mismatch Repair Proteins Associated with Acquisition of Microsatellite Instability in a Clonal Model of Human T Lymphocyte Aging

Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells

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