Non-enzymatic post-translational protein modifications and proteostasis network deregulation in carcinogenesis

Trougakos, Ioannis P.; Sesti, Fabiola; Tsakiri, Eleni N.; Gorgoulis, Vassilis G.

doi:10.1016/j.jprot.2013.02.024

Cited by 51 publications

(84 citation statements)

References 337 publications

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“…This transition could promote an appropriate interaction with CLU. In summary, these three molecular chaperones (Bip, CLU and Hsc70) may be part of a proteostasis network [24,25,43] to realize trafficking, binding and refolding of denatured intracellular proteins upon cellular stress conditions.…”

Section: Discussionmentioning

confidence: 99%

“…This, in contrast, is believed to be mediated by a few organized regions within the sCLU-protein which can bind to certain receptors of the LRP (lipoprotein receptor-related protein)-receptor family on the surface of vital cells [9,17,38,39,40]. Thereby, sCLU initiates the endocytic uptake and removal of misfolded protein aggregates, thus rendering it a key player during the homeostasis of the proteome, a process which is also termed proteostasis [24,41,42,43]. Furthermore, recent studies suggest that sCLU is an important player for modulating MAPK/Erk and PI3K/Akt signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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The Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment

Rohne

Prochnow

Wolf

et al. 2014

Cell Physiol Biochem

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Background/Aims: Clusterin (CLU), also known as Apolipoprotein J (ApoJ) is a highly glycosylated extracellular chaperone. In humans it is expressed from a broad spectrum of tissues and related to a plethora of physiological and pathophysiological processes, such as Alzheimer's disease, atherosclerosis and cancer. In its dominant form it is expressed as a secretory protein (secreted CLU, sCLU). During its maturation, the sCLU-precursor is N-glycosylated and cleaved into an α- and a β-chain, which are connected by five symmetrical disulfide bonds. Recently, it has been demonstrated that besides the predominant sCLU, rare intracellular CLU forms are expressed in stressed cells. Since these forms do not enter or complete the secretory pathway, they are not proteolytically modified and show either no or only core glycosylation. Due to their sparsity, these intracellular forms are functionally poorly characterized. To evaluate the function(s) of these stress-related intracellular forms, we investigate for the first time the impact of proteolytic cleavage, differential glycosylation and the influence of the redox environment on the chaperone activity of CLU. Methods: Non-cleavable sCLU was generated by expression from a mutant construct of sCLU, in which the furin-like proprotein convertase (PC) recognition site was modified. After purification of recombinant uncleaved sCLU from the medium of over-expressing cells, we performed chaperone activity assays to compare the activities of wild-type (cleaved) and uncleaved mutant sCLU. Additionally, this approach enabled us to investigate the role of carbohydrates, the proteolytic maturation and reducing conditions on CLU chaperone activity. Further, we characterized the differentially treated CLU forms by using MALDI-TOF, CD-spectroscopy and Western blotting in addition to the functional assay. Results: We show that the PC-cleavage is dispensable for sCLU chaperone activity. Moreover, our data demonstrate that while fully deglycosylated sCLU lacks chaperone activity, partially deglycosylated sCLU is still capable of solubilizing target proteins. Most importantly, we here demonstrate for the first time that uncleaved sCLU is highly sensitive towards reducing conditions. Conclusions: Our study provides evidence that unglycosylated intracellular CLU forms cannot exhibit a chaperone activity compared to sCLU. Additionally, we support recent postulates that glycosylated intracellular CLU forms may act as a redox sensor under oxidative stress conditions. Furthermore, we conclude that the proteolytic cleavage of sCLU is important to maintain full chaperone activity, i.e. in the presence of necrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment

Rohne

Prochnow

Wolf

et al. 2014

Cell Physiol Biochem

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“…Considering that most (if not all) of the critical cellular functions are performed by sophisticated protein machines (Trougakos, 2013;Trougakos et al, 2013) it is not surprising that homeostasis of the proteome (proteostasis) is critical for cellular functionality and consequently for the overall health span of the multicellular system, namely the organism. The numerous…”

Section: Introductionmentioning

confidence: 99%

“…To retain proteome stability, cells have developed a modular, yet integrated system which ensures general proteome quality control and it is called the proteostasis network (PN) (Morimoto, 2008;Trougakos et al, 2013;Niforou et al, 2014). The PN curates the basal functionality of the proteome and it also responds to conditions of proteotoxic stress by addressing the triage decision of fold, hold, or degrade.…”

Section: Introductionmentioning

confidence: 99%

“…PN constitutes of several complex protein machines that ensure normal proteome synthesis and recycling, or respond to conditions of proteotoxic stress by launching the proteome damage responses (PDRs), which, first identify, and then, either rescue or degrade unfolded, misfolded, or nonnative polypeptides. Additional integrated modules of the PN can be considered the regulatory pathways of the cellular stress (e.g., heat or oxidative) responses which mobilize the proteome caretakers; mitotic cells can also dilute proteome damage by mitosis (Niforou et al, 2014;Trougakos et al, 2013). As it is now realized there is significant cross talk between the various PN constituent components; this cross talk appears to be critical for the maintenance of cellular proteostasis and proteome stability (Balantinou et al, 2009;Fusco et al, 2012;K€ astle and Grune, 2012;LTw et al, 2013;Sun et al, 2009;Trougakos et al, 2013;Tsakiri et al, 2013a,b,c).…”

Section: Introductionmentioning

confidence: 99%

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The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

Tsakiri

Trougakos

2015

International Review of Cell and Molecular Biology

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Heat shock protein beta 3 (HSPB3) is an unfavorable molecular biomarker in colorectal adenocarcinoma

Kalioraki

Artemaki

Sklirou

et al. 2019

Molecular Carcinogenesis

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Small heat shock proteins (sHSPs) participate in numerous cellular functions including cell signaling, differentiation, and apoptosis. Deregulation of the physiological expression level of sHSPs has been associated with several malignancies. Heat shock protein beta 3 (HSPB3) is the third member of the sHSP family in human and is mainly expressed in skeletal and smooth muscles. In this study, we investigated the potential prognostic significance of HSPB3 expression in colorectal adenocarcinoma, the most frequent type of colorectal cancer. For this purpose, we isolated total RNA from 188 colorectal adenocarcinoma specimens and 68 paired noncancerous ones. After reverse transcription of 2 μg total RNA, we quantified HSPB3 levels by using an in-house-developed real-time quantitative polymerase chain reaction method, based on the SYBR Green chemistry. Comparison of HSPB3 levels among 68 pairs of colorectal tumors and their adjacent noncancerous mucosae uncovered the downregulation of HSPB3 expression in the majority of malignant colorectal tumors. More importantly, high HSPB3 expression is associated with poor relapse-free survival (RFS) and overall survival (OS) of patients with colorectal adenocarcinoma. Multivariable Cox regression analysis revealed that HSPB3 overexpression could serve as an adverse prognostic biomarker in colorectal adenocarcinoma, independent of tumor location, histological grade, and TNM stage. Patients' stratification according to tumor location, histological grade, and TNM stage revealed that high HSPB3 messenger RNA expression retains its unfavorable prognostic potential regarding OS, in particular groups of patients with substantially different prognosis. In conclusion, high HSPB3 expression is associated with poor RFS and OS of patients with colorectal adenocarcioma, independently of clinicopathological prognosticators. K E Y W O R D S colorectal cancer, HSPB3, molecular tumor markers, prognosis, prognostic biomarkers. Abbreviations: B2M, Beta-2-microglobulin; cDNA, Complementary DNA; CRC, Colorectal cancer; HSPB3, Heat shock protein beta 3; mRNA, Messenger RNA; OS, Overall survival; qPCR, Quantitative polymerase chain reaction; RFS, Relapse-free survival; RQU, Relative quantification unit; sHSP, Small heat shock protein. Maria-Anna Kalioraki and Pinelopi I. Artemaki equally contributed to the study. How to cite this article: Kalioraki M-A, Artemaki PI, Sklirou AD, et al. Heat shock protein beta 3 (HSPB3) is an unfavorable molecular biomarker in colorectal adenocarcinoma. Molecular Carcinogenesis. 2020;59:116-125.

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Non-enzymatic post-translational protein modifications and proteostasis network deregulation in carcinogenesis

Cited by 51 publications

References 337 publications

The Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment

The Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment

The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

Heat shock protein beta 3 (HSPB3) is an unfavorable molecular biomarker in colorectal adenocarcinoma

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