TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations

Hua, Fang; Li, Ké; Yu, Jiankun; Lv, Xiao Xi; Yan, Jun; Zhang, Xiao Wei; Sun, Wei; Lin, Heng; Shang, Shuang; Wang, Feng; Cui, Bing; Mu, Rong; Huang, Bo; Jiang, Jian; Hu, Zhuo Wei

doi:10.1038/ncomms8951

Cited by 114 publications

(142 citation statements)

References 55 publications

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“…p62 recruits protein aggregates as substrate to autophagic membranes to form autophagosomes and thus promotes their degradation (24). In addition, p62 itself is a substrate for autophagic degradation and accumulates upon inhibition of autophagy (24,25).…”

Section: Discussionmentioning

confidence: 99%

Autophagy-associated proteins BAG3 and p62 in testicular cancer

et al. 2015

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Abstract. Testicular germ cell tumors (TGCT) represent the most common malignant tumor group in the age group of 20 to 40-years old men. The potentially curable effect of cytotoxic therapy in TGCT is mediated mainly by the induction of apoptosis. Autophagy has been discussed as an alternative mechanism of cell death but also of treatment resistance in various types of tumors. However, in TGCT the expression and role of core autophagy-associated factors is hitherto unknown. We designed the study in order to evaluate the potential role of autophagy-associated factors in the development and progression of testicular cancers. Eighty-four patients were assessed for autophagy (BAG3, p62) and apoptosis (cleaved caspase 3) markers using immunohistochemistry (IHC) on tissue microarrays. In addition, western blot analyses of frozen tissue of seminoma and non-seminoma were performed. Our findings show that BAG3 was significantly upregulated in seminoma as compared to non-seminoma but not to normal testicular tissue. No significant difference of p62 expression was detected between neoplastic and normal tissue or between seminoma and non-seminoma. BAG3 and p62 showed distinct loco-regional expression patterns in normal and neoplastic human testicular tissues. In contrast to the autophagic markers, apoptosis rate was significantly higher in testicular tumors as compared to normal testicular tissue, but not between different TGCT subtypes. The present study, for the first time, examined the expression of central autophagy proteins BAG3 and p62 in testicular cancer. Our findings imply that in general apoptosis but not autophagy induction differs between normal and neoplastic testis tissue. IntroductionThe effect of cytotoxic treatment in testicular tumors is mainly moderated by the induction of apoptosis (1). Due to the rapid response after exposure to chemotherapeutic agents an intact and effective apoptotic pathway in most testicular cancers is assumed (2). Nevertheless, various patients show complex clinical courses, including tumors with chemoresistence and thus lower apoptosis rates (3). Recent studies have shown that the elimination of cells may be also conducted using the alternative cell death pathway ʻautophagyʼ (4,5).Autophagy is an evolutionarily conserved, pervasive and multi-step ʻself-eatingʼ process, by which cytosolic material is sequestered in a double-lipid membrane, delivered to the lysosome for degradation and digested to provide energy and to build the foundation for cell-survival (6). While autophagy has for long been considered to be a bulk degradation process, recent discoveries show that it rather displays a sophisticated portfolio of selectivity provided by different molecular strategies such as the detection of several autophagy receptor proteins, including pacemaker molecules such as p62 (SQSTM1) and BCL2-associated athanogene 3 (BAG3) (7-9). To the best of our knowledge, no study has been published to date that examined the expression of the cohesive autophagy proteins BAG3 and p62 in testicular can...

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Section: Discussionmentioning

confidence: 99%

Autophagy-associated proteins BAG3 and p62 in testicular cancer

et al. 2015

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“…Recently, researchers have found that TRB3, which is closely associated with diabetes related cancer, interacts with autophagic receptor SQSTM1 (p62) and hinders SQSTM1 to bind to LC3 and ubiquitinated substrates, and therefore produces potent antitumour efficacies against tumor growth and metastasis [89]. …”

Section: Roles Of Energy Sensing Pathways In Colorectal Cancer In mentioning

confidence: 99%

Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?

Yang

Nishihara

Zhang

et al. 2017

Journal of Diabetes and its Complications

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The recently rapid increase of obesity and type 2 diabetes mellitus has caused great burden to our society. A positive association between type 2 diabetes and risk of colorectal cancer has been reported by increasing epidemiological studies. The molecular mechanism of this connection remains elusive. However, type 2 diabetes may result in abnormal carbohydrate and lipid metabolism, high levels of circulating insulin, insulin growth factor-1, and adipocytokines, as well as chronic inflammation. All these factors could lead to the alteration of energy sensing pathways such as the AMP activated kinase (PRKA), mechanistic (mammalian) target of rapamycin (mTOR), SIRT1, and autophagy signaling pathways. The resulted impaired SIRT1 and autophagy signaling pathway could increase the risk of gene mutation and cancer genesis by decreasing genetic stability and DNA mismatch repair. The dysregulated mTOR and PRKA pathway could remodel cell metabolism during the growth and metastasis of cancer in order for the cancer cell to survive the unfavorable microenvironment such as hypoxia and low blood supply. Moreover, these pathways may coupling metabolic and epigenetic alterations that is central to oncogenic transformation. Further researches including molecular pathologic epidemiologic studies are warranted to better address the precise links between these two important diseases.

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“…Similarly, there is no consensus in the current literature about the oncogenic vs. tumour suppressor role of tribbles proteins12181920, suggesting that an important aspect of their activity may be context or cell type dependent. We believe that many of the currently conflicting published studies might be explained and reconciled if we understood the molecular basis of specificity and redundancy between tribbles proteins.…”

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confidence: 99%

Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways

Guan

Shuaib

León

et al. 2016

Sci Rep

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Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways.

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TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations

Cited by 114 publications

References 55 publications

Autophagy-associated proteins BAG3 and p62 in testicular cancer

Autophagy-associated proteins BAG3 and p62 in testicular cancer

Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?

Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways

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