Regulation of Clusterin Gene Expression

Garcia-Aranda, Marilina; Serrano, Antonio; Redondo, Maximino

doi:10.2174/1389203718666170918155247

Cited by 24 publications

(29 citation statements)

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“…Clusterin, encoded by the CLU gene, is an extracellular chaperone that prevents aggregation of non-native proteins. Moreover, it was demonstrated that clusterin is involved in various cellular processes, including apoptosis, cell cycle regulation, and DNA repair [23]. Overexpression of the CLU gene in six MPS types suggests that this might be a response to stress conditions caused by cell dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Gaffke

Pierzynowska

Podlacha

et al. 2020

IJMS

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Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes’ expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes.

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Section: Discussionmentioning

confidence: 99%

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Gaffke

Pierzynowska

Podlacha

et al. 2020

IJMS

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“…As shown in Figure 8c upregulated in stress-induced cells, such as various tumor cells and renal TEC. 32,33 In addition, CLU expression in Mφ was weak or undetectable in the immunohistochemistry of lung tissue, 34 but was upregulated in mature Mφ in human breast tumor tissues and the RAW264.7 Mφ cell line. 35 In this study, CLU proteins were detected in THP1 human monocytes, RAW264.7 Mφ and peritoneal Mφ isolated from WT mice, and their expression was upregulated in THP1 cells and RAW264.7 cells following hypoxia.…”

Section: Clu Is Associated With Decreased Polarization To M1 After LImentioning

confidence: 99%

Clusterin regulates macrophage expansion, polarization and phagocytic activity in response to inflammation in the kidneys

Wang

Zhao

Guan

et al. 2020

Immunol. Cell Biol.

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Clusterin (CLU) is a multifunctional protein localized extracellularly and intracellularly. Although CLU-knockout (KO) mice are more susceptible to renal ischemia-reperfusion injury (IRI), the mechanisms underlying the actions of CLU in IRI are not fully understood. Macrophages are key regulators of IRI severity and tissue repair. Therefore, we investigated the role of CLU in macrophage polarization and phagocytosis. Renal IRI was induced in wild-type (WT) or CLU-KO C57BL/6 mice by clamping the renal pedicles for 30 min at 32°C. Peritoneal macrophages were activated via an intraperitoneal injection of lipopolysaccharide (LPS). Renal tissue damage was examined using histology, whereas leukocyte phenotypes were assessed using flow cytometry and immunohistochemistry. We found that monocytes/macrophages expressed the CLU protein that was upregulated by hypoxia. The percentages of macrophages (F4/80 + , CD11b + or MAC3 +) infiltrating the kidneys of WT mice were significantly less than those in CLU-KO mice after IRI. The M1/M2 phenotype ratio of the macrophages in WT kidneys decreased at day 7 post-IRI when the injury was repaired, whereas that in KO kidneys increased consistently as tissue injury persisted. In response to LPS stimulation, WT mice produced fewer M1 macrophages, but not M2, than the control did. Phagocytosis was stimulated by CLU expression in macrophages compared with the CLU null controls and by the exogenous CLU protein. In conclusion, CLU suppresses macrophage infiltration and proinflammatory M1 polarization during the recovery period following IRI, and enhances phagocytic activity, which may be partly responsible for tissue repair in the kidneys of WT mice after injury.

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“…Another major impediment to immunotherapy success in breast cancer patients is the selection of apoptosis-resistant cells, which constitutes one of the hallmarks of cancer [17]. Since both chemo-and immunotherapies directly or indirectly activate the cellular apoptosis machinery, tumor sensitivity to anti-cancer treatments will significantly depend on the level of expression of anti-apoptotic proteins [24] in general and, more specifically, on the existence of a pro-survival profile characterized by an increased ratio between anti-/pro-apoptotic proteins [24,90,91].…”

Section: Changes In Breast Tumor Cellsmentioning

confidence: 99%

Immunotherapy: A Challenge of Breast Cancer Treatment

García-Aranda

Redondo

2019

Cancers

Self Cite

131

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Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the significant benefit of the use of conventional chemotherapy and monoclonal antibodies in the prognosis of breast cancer patients and although the recent approval of the anti-PD-L1 antibody atezolizumab in combination with chemotherapy has been a milestone for the treatment of patients with metastatic triple-negative breast cancer, immunologic treatment of breast tumors remains a great challenge. In this review, we summarize current breast cancer classification and standard of care, the main obstacles that hinder the success of immunotherapies in breast cancer patients, as well as different approaches that could be useful to enhance the response of breast tumors to immunotherapies.

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Regulation of Clusterin Gene Expression

Cited by 24 publications

References 0 publications

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Clusterin regulates macrophage expansion, polarization and phagocytic activity in response to inflammation in the kidneys

Immunotherapy: A Challenge of Breast Cancer Treatment

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