FBXW7-Induced MTOR Degradation Forces Autophagy to Counteract Persistent Prion Infection

Xu, Yin; Tian, Chan; Sun, Jing; Zhang, Jin; Ren, Ke; Fan, Xueyu; Wang, Ke; Wang, Hui; Yan, Yonggao; Cao, Chen; Shi, Qi; Dong, Xiao-Ping

doi:10.1007/s12035-014-9028-7

Cited by 31 publications

(26 citation statements)

References 34 publications

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“…5a, both the signals of Hsc70 and LAMP2a were obviously weaker in SMB-S15 cells than in SMB-PS cells. Meanwhile, enhanced LC3-II level and reduced p62 level were observed in SMB-S15 cells as described previously [23,24]. It indicates a depression of CMA and an activation of macroautophagy during the replication of prion in the cultured cells.…”

Section: Downregulation Of Chaperone-mediated Autophagy In the Scrapisupporting

confidence: 82%

Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

et al. 2016

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Polo-like kinase 3 (PLK3) is the main cause of cell cycle reentry-related neuronal apoptosis which has been implicated in the pathogenesis of prion diseases. Previous work also showed the regulatory activity of exogenous PLK3 on the degradation of PrP (prion protein) mutants and pathogenic PrP; however, the precise mechanisms remain unknown. In this study, we identified that the overexpression of PLK3-mediated degradation of PrP mutant and PrP was repressed by lysosome rather than by proteasomal and macroautophagy inhibitors. Core components of chaperone-mediated autophagy (CMA) effectors, lysosome-associated membrane protein type 2A (LAMP2a), and heat shock cognate protein 70 (Hsc70) are markedly decreased in the HEK293T cells expressing PrP mutant and scrapie-infected cell line SMB-S15. Meanwhile, PrP mutant showed ability to interact with LAMP2a and Hsc70. Overexpression of PLK3 sufficiently increased the cellular levels of LAMP2a and Hsc70, accompanying with declining the accumulations of PrP mutant and PrP. The kinase domain (KD) of PLK3 was responsible for elevating LAMP2a and Hsc70. Knockdown of endogenous PLK3 enhanced the activity of macroautophagy in the cultured cells. Moreover, time-dependent reductions of LAMP2a and Hsc70 were also observed in the brain tissues of hamster-adapted scrapie agent 263K-infected hamsters, indicating an impairment of CMA during prion infection. Those data indicate that the overexpression of PLK3-mediated degradation of abnormal PrP is largely dependent on CMA pathway.

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Section: Downregulation Of Chaperone-mediated Autophagy In the Scrapisupporting

confidence: 82%

Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

et al. 2016

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“…Therefore, highly expressed FBXW7 in RCC cell lines can induce ubiquitination and degradation of c-Myc and c-Jun protein and suppress tumor cell growth. Furthermore, mTOR is also the target protein of FBXW7 and can be degraded by ubiquitination [19,20]. mTOR is a protein kinase, which induces cell growth and division through regulating protein synthesis and autophagy [21].…”

Section: Resultsmentioning

confidence: 99%

FBXW7 overexpression suppresses renal cancer cell proliferation and induces apoptosis

Lin

Zhao

et al. 2015

Med Oncol

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FBXW7 gene (F-box and WD-40 domain protein 7) is also named HCDC4 and is a significant tumor suppressor gene, which can regulate human cell cycle, proliferation and differentiation. In this study, we tend to investigate protein expression and related biological functions of FBXW7 gene. FBXW7 expression level in renal cell carcinoma (RCC) tissues is highly related to its clinical pathologic grade (P = 0.0094) and TNM phase (P = 0.0080) and is highly lower than in paracancerous normal tissues through immunohistochemistry study. FBXW7 high-expression patients have overall better prognosis than low-expression patients (P < 0.001). After transfected with FBXW7 plasmid, the RCC cell lines ACHN and A704 showed a depressed proliferation activity and high proportion of apoptosis through CCK8, colony formation and flow cytometry assay studies. By Western blot analysis, expression of cell proliferation-activating protein c-Myc and c-Jun is downregulated in FBXW7 high-expression RCC compared with negative control. These data suggested that FBXW7 is a significant tumor suppressor gene in RCC.

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“…humans [18,29]. However, some other proteins that abnormally expressed in the prion infected individuals may remain unchanged in the prion infected cells, e.g., p21-activated kinases 3 (PAK3) and its associated factors (Rac1/cdc42, c-raf and phosphor-c-raf) [30], aB-crystalline [31], brain-derived neurotrophic factor (BDNF) and the relevant factors (TrkB, p-TrkB, GRB2 and p57NTR) [32], or not so vigorously changed, such as A disintegrin and metalloproteinase (ADAM10) [33], glucose transporter 3 (GLUT3) [34], Polo-like kinases 3 (PLK3) [35].…”

Section: Discussionmentioning

confidence: 99%

“…SMB-PS and SMB-S15 cell lines were obtained from the Roslin Institute (UK) and cultured in Dulbecco's modified Eagle's medium (Gibco, USA) supplemented with 12% fetal bovine serum (FBS) (AusgeneX, Australia) according to the protocol described previously [17,18]. Cell line SMB-S15 was originally infected with scrapie strain Chandler and the PrP Sc replication was persistently observed during cell passages.…”

Section: Cell Culture and Cell Lysatesmentioning

confidence: 99%

Decrease of RyR2 in the prion infected cell line and in the brains of the scrapie infected mice models and the patients of human prion diseases

Shi

et al. 2018

Prion

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The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected cell line SMB-S15 and its infected mice were tested. RyR2 specific Western blots revealed markedly decreased RyR2 levels both in the cells and in the brains of infected mice. Assays of the brain samples of other scrapie (agents 139A and ME7) infected mice collected at different time-points during incubation period showed time-dependent decreases of RyR2. Immunofluorescent assays (IFA) verified that the expression of RyR2 locates predominantly in cytoplasm of SMB cells and overlapped with the neurons in the brain slices of mice. Furthermore, significant down-regulation of RyR2 was also detected in the postmortem cortical brains of the patients of various types of human prion diseases, including sporadic Creutzfeldt-Jakob disease (sCJD), fatal familial insomnia (FFI) and G114V-genetic CJD. Our data here propose the evidences of remarkably decreased brain RyR2 at terminal stages of both human prion diseases and prion infected rodent models. It also highlights that the therapeutic strategy with antagonist of RyRs in AD may not be suitable for prion disease.

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FBXW7-Induced MTOR Degradation Forces Autophagy to Counteract Persistent Prion Infection

Cited by 31 publications

References 34 publications

Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

FBXW7 overexpression suppresses renal cancer cell proliferation and induces apoptosis

Decrease of RyR2 in the prion infected cell line and in the brains of the scrapie infected mice models and the patients of human prion diseases

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