Expression and clinical role of small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) as a novel cell cycle protein in NSCLC

Xue, Qun; Lv, Liting; Wan, Chunhua; Chen, Buyou; Li, Mei; Ni, Tianming; Liu, Yifei; Liu, Yanhua; Xia, Cong; Zhou, Yiqun; Ni, Runzhou; Mao, Guoxin

doi:10.1007/s00432-013-1474-5

Cited by 17 publications

(10 citation statements)

References 26 publications

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“…7). Interestingly, several recent reports correlate increases in SGTA expression with the proliferation of several forms of cancer, although the molecular basis for this observation remains to be defined (Lu et al, 2014; Philp et al, 2013; Xue et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

SGTA regulates the cytosolic quality control of hydrophobic substrates

Wunderley

Leznicki

Payapilly

et al. 2014

Journal of Cell Science

114

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Hydrophobic amino acids are normally shielded from the cytosol and their exposure is often used as an indicator of protein misfolding to enable the chaperone-mediated recognition and quality control of aberrant polypeptides. Mislocalised membrane proteins (MLPs) represent a particular challenge to cellular quality control, and, in this study, membrane protein fragments have been exploited to study a specialised pathway that underlies the efficient detection and proteasomal degradation of MLPs. Our data show that the BAG6 complex and SGTA compete for cytosolic MLPs by recognition of their exposed hydrophobicity, and the data suggest that SGTA acts to maintain these substrates in a non-ubiquitylated state. Hence, SGTA might counter the actions of BAG6 to delay the ubiquitylation of specific precursors and thereby increase their opportunity for successful post-translational delivery to the endoplasmic reticulum. However, when SGTA is overexpressed, the normally efficient removal of aberrant MLPs is delayed, increasing their steady-state level and promoting aggregation. Our data suggest that SGTA regulates the cellular fate of a range of hydrophobic polypeptides should they become exposed to the cytosol.

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Section: Discussionmentioning

confidence: 99%

SGTA regulates the cytosolic quality control of hydrophobic substrates

Wunderley

Leznicki

Payapilly

et al. 2014

Journal of Cell Science

114

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“…SGTA is required for progress through cell division and promotes cell proliferation (Winnefeld et al 2004). Recent studies demonstrated that overexpression of SGTA was frequent in lung cancer, human hepatocellular carcinoma and esophageal squamous cell carcinoma (Xue et al 2013;Lu et al 2014;Yang et al 2014). These studies have shown a high status and implied that SGTA may play an important role in cancer progression and metastasis.…”

Section: Introductionmentioning

confidence: 98%

Expression and prognostic role of SGTA in human breast carcinoma correlates with tumor cell proliferation

Zhu

et al. 2014

J Mol Hist

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Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) was reported to be implicated in various cellular processes and involved in control of cell cycle regulation and transcription. It may play a critical role in oncogenesis. In this study, to investigate the potential roles of SGTA in breast cancer, expression patterns, interaction and the correlation with clinical/prognostic factors of SGTA and Ki-67 were examined among patients with breast cancer. Immunohistochemistry and Western blot analysis were performed for SGTA in 100 breast carcinoma samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine the prognostic significance. We found that SGTA was overexpressed in breast carcinoma compared with the adjacent normal tissues. High expression of SGTA was positively associated with histological grade (P = 0.002) and Ki-67 (P = 0.001). Univariate analysis showed that SGTA expression was associated with a poor prognosis (P = 0.002). Kaplan-Meier survival curves of the study population showed that high expression level of SGTA significantly correlated with short-term survival. While in vitro, SGTA depletion by small interfering RNA inhibited cell proliferation and cell cycle in breast cancer cell lines. Western blot analyses showed that SGTA depletion decreased cyclin A, cyclin B and CDK2, whereas increased p27 levels. Additionally, treatment of phosphatidylinositol 3-kinase inhibitor LY294002 could arrest cells growth and diminish SGTA expression. These results suggested that SGTA overexpression was involved in the pathogenesis of breast cancer which might serve as a future target for novel treatment in breast cancer.

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“…In addition, SGTA contains a central tetratricopeptide repeat (TPR) domain (that can interact with the C-termini of Hsp70 and Hsp90 molecular chaperones as well as viral proteins and hormone receptors) and a glutamine rich region towards the C-terminus [13]. Although all of its roles have yet to be fully elucidated, SGTA looks to be an important protein for health and disease, recently found to be up-regulated in certain cancers (oesophageal [14], liver [15], ovarian [16] and lung [17]). Recent studies of SGTA, and its yeast homologue Sgt2, have demonstrated that SGTA interacts with the BAG6 complex's two ubiquitin-like (UBL) domains via a ubiquitin-like binding domain (UBD).…”

Section: Introductionmentioning

confidence: 99%

Solution Structure of the SGTA Dimerisation Domain and Investigation of Its Interactions with the Ubiquitin-Like Domains of BAG6 and UBL4A

et al. 2014

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Background The BAG6 complex resides in the cytosol and acts as a sorting point to target diverse hydrophobic protein substrates along their appropriate paths, including proteasomal degradation and ER membrane insertion. Composed of a trimeric complex of BAG6, TRC35 and UBL4A, the BAG6 complex is closely associated with SGTA, a co-chaperone from which it can obtain hydrophobic substrates. Methodology and Principal Findings SGTA consists of an N-terminal dimerisation domain (SGTA_NT), a central tetratricopeptide repeat (TPR) domain, and a glutamine rich region towards the C-terminus. Here we solve a solution structure of the SGTA dimerisation domain and use biophysical techniques to investigate its interaction with two different UBL domains from the BAG6 complex. The SGTA_NT structure is a dimer with a tight hydrophobic interface connecting two sets of four alpha helices. Using a combination of NMR chemical shift perturbation, isothermal titration calorimetry (ITC) and microscale thermophoresis (MST) experiments we have biochemically characterised the interactions of SGTA with components of the BAG6 complex, the ubiquitin-like domain (UBL) containing proteins UBL4A and BAG6. We demonstrate that the UBL domains from UBL4A and BAG6 directly compete for binding to SGTA at the same site. Using a combination of structural and interaction data we have implemented the HADDOCK protein-protein interaction docking tool to generate models of the SGTA-UBL complexes. Significance This atomic level information contributes to our understanding of the way in which hydrophobic proteins have their fate decided by the collaboration between SGTA and the BAG6 complex.

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Expression and clinical role of small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) as a novel cell cycle protein in NSCLC

Abstract: These findings suggested that SGTA might play an important role in promoting the tumorigenesis of NSCLC, and thus be a promising therapeutic target to prevent NSCLC progression.

Cited by 17 publications

References 26 publications

SGTA regulates the cytosolic quality control of hydrophobic substrates

SGTA regulates the cytosolic quality control of hydrophobic substrates

Expression and prognostic role of SGTA in human breast carcinoma correlates with tumor cell proliferation

Solution Structure of the SGTA Dimerisation Domain and Investigation of Its Interactions with the Ubiquitin-Like Domains of BAG6 and UBL4A

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