Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors

Papoudou‐Bai, Alexandra; Barbouti, Alexandra; Galani, Vasiliki; Stefanaki, Kalliopi; Rontogianni, Dimitra; Kanavaros, Panagiotis

doi:10.1007/s10238-015-0344-7

Cited by 6 publications

(4 citation statements)

References 115 publications

(323 reference statements)

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“…Although this theory requires experimental support, it should be taken into consideration as it raises questions for the putative beneficial effect of restoring the thymic activity in elderly. Finally, the exact role of cellular senescence during thymic tumorigenesis (thymic epithelial tumors) [176,177], given its bimodal mode of action in cancer, can now be further examined with the use of the novel GL13 compound in clinical material. In this context, it would also be interesting to investigate the implication of senescence in the response to therapy and regression of thymic tumors in order to improve the outcome of patients.…”

Section: Discussionmentioning

confidence: 99%

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution

Barbouti

Vasileiou

Evangelou

et al. 2020

Oxidative Medicine and Cellular Longevity

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The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed “thymic involution.” A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution.

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Section: Discussionmentioning

confidence: 99%

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution

Barbouti

Vasileiou

Evangelou

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Apoptosis is a central process in thymus physiology, because about 90% of thymocytes die, leaving only 10% to complete their maturation and migrate out towards peripheral lymphoid organs to mount a functional immune response [ 1 , 2 ]. Two different thymic processes direct the death of thymocytes by apoptosis: (1) negative selection, by which about 10% of the putative autoreactive thymocytes die before leaving the thymus [ 3 , 4 ], and (2) death by neglect, by which 80% of thymocytes with insufficient affinity for self-antigens die because they are not selected for, either positively or negatively [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes

Muscari

Adorisio

Liberati

et al. 2020

Journal of Translational Autoimmunity

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Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous regulators of thymic apoptosis. Among these, glucocorticoid-induced leucine zipper (GILZ) is strongly upregulated in the thymus. We have previously demonstrated that GILZ decreases Bcl-xL expression, activates caspase-8 and caspase-3, and augments apoptosis in mice thymocytes. To better understand the causal links between glucocorticoids, GILZ, Bcl-xL, caspase-8, and caspase-3, we analyzed the thymocytes of Bcl-xL-overexpressing transgenic mice with or without glucocorticoid stimulation in vitro . Overexpression of Bcl-xL inhibited the glucocorticoid-induced up-regulation of GILZ in murine thymocytes as well as the glucocorticoid-dependent activation of caspase-8 and caspase-3. By contrast, no appreciable change in caspase-9 activation was observed upon Bcl-xL overexpression. Thus, these experiments highlighted a novel thymocyte apoptotic pathway in which Bcl-xL overexpression inhibited the glucocorticoid-induced activation of caspase-8 and caspase-3, but not caspase-9, as well as the accumulation of GILZ protein. These findings, together with our previous results showing that caspase-8 protects GILZ from proteasomal degradation, suggest the presence of a glucocorticoid-induced apoptosis self-amplification loop in which GILZ decreases Bcl-xL expression with a subsequent activation of caspase-8 and caspase-3; caspase-8 activation then enhances the stability and accumulation of GILZ and ensures the unimpeded and irreversible progression of apoptosis. By contrast, inappropriate increases in Bcl-xL levels could have catastrophic effects on thymic apoptosis as it would shut down caspase-8/3 activation, diminish the expression of GILZ, and impair the fine control necessary for thymic generation of a healthy immune repertoire.

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“…In total, we identified 8 lysine modification-related driver proteins, and 37.5% (3 out of 8) of them were proven by previous publication (Heyd and Lynch, 2011 ; Blachly and Baiocchi, 2014 ; Park et al, 2014 ; Papoudou-Bai et al, 2016 ). Again, the CCAR2 in our identified list is also known to correlate with patient prognosis (Park et al, 2014 ; Papoudou-Bai et al, 2016 ). In this regard, we can conclude that our method is sensitive to finding potential gene products that have strong clinical implications in cancer patients.…”

Section: Resultsmentioning

confidence: 65%

Pan-Cancer Analysis Reveals the Functional Importance of Protein Lysine Modification in Cancer Development

et al. 2018

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Large-scale tumor genome sequencing projects have revealed a complex landscape of genomic mutations in multiple cancer types. A major goal of these projects is to characterize somatic mutations and discover cancer drivers, thereby providing important clues to uncover diagnostic or therapeutic targets for clinical treatment. However, distinguishing only a few somatic mutations from the majority of passenger mutations is still a major challenge facing the biological community. Fortunately, combining other functional features with mutations to predict cancer driver genes is an effective approach to solve the above problem. Protein lysine modifications are an important functional feature that regulates the development of cancer. Therefore, in this work, we have systematically analyzed somatic mutations on seven protein lysine modifications and identified several important drivers that are responsible for tumorigenesis. From published literature, we first collected more than 100,000 lysine modification sites for analysis. Another 1 million non-synonymous single nucleotide variants (SNVs) were then downloaded from TCGA and mapped to our collected lysine modification sites. To identify driver proteins that significantly altered lysine modifications, we further developed a hierarchical Bayesian model and applied the Markov Chain Monte Carlo (MCMC) method for testing. Strikingly, the coding sequences of 473 proteins were found to carry a higher mutation rate in lysine modification sites compared to other background regions. Hypergeometric tests also revealed that these gene products were enriched in known cancer drivers. Functional analysis suggested that mutations within the lysine modification regions possessed higher evolutionary conservation and deleteriousness. Furthermore, pathway enrichment showed that mutations on lysine modification sites mainly affected cancer related processes, such as cell cycle and RNA transport. Moreover, clinical studies also suggested that the driver proteins were significantly associated with patient survival, implying an opportunity to use lysine modifications as molecular markers in cancer diagnosis or treatment. By searching within protein-protein interaction networks using a random walk with restart (RWR) algorithm, we further identified a series of potential treatment agents and therapeutic targets for cancer related to lysine modifications. Collectively, this study reveals the functional importance of lysine modifications in cancer development and may benefit the discovery of novel mechanisms for cancer treatment.

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Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors

Cited by 6 publications

References 115 publications

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution

Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes

Pan-Cancer Analysis Reveals the Functional Importance of Protein Lysine Modification in Cancer Development

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