HIF-1 Regulation of Chondrocyte Apoptosis: Induction of the Autophagic Pathway

Bohensky, Jolene; Shapiro, Irving M.; Leshinsky, Serge; Terkhorn, Shawn P.; Adams, Christopher S.; Srinivas, Vickram

doi:10.4161/auto.3708

Cited by 139 publications

(129 citation statements)

References 21 publications

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“…FoxO3 has been shown to directly regulate the expression of Gabarapl1, LC3b, and Atg12l in myotubes (66). Other findings have confirmed the ability of HIF-1␣ to either indirectly regulate both BECN1/Atg6 and Atg5 (4,64) or directly bind the BNIP3 promoter (58). Interestingly, a most recent work showed that E2F1 binds the Atg1/ULK1, MAPLC3, and DRAM1 promoters, increasing their expression and regulating autophagy (44).…”

mentioning

confidence: 62%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

235

179

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Recently, autophagy has emerged as a critical process in the control of T-cell homeostasis. Given the pivotal role of NF-B in the signaling events of T cells, we have analyzed and unveiled a conserved NF-B binding site in the promoter of the murine and human BECN1 autophagic gene (Atg6). Accordingly, we demonstrate that the NF-B family member p65/RelA upregulates BECN1 mRNA and protein levels in different cellular systems. Moreover, p65-mediated upregulation of BECN1 is coupled to increased autophagy. The newly identified B site in the BECN1 promoter specifically interacts with p65 both in vitro and in living Jurkat cells upon phorbol myristate acetate (PMA)-ionomycin stimulation, where p65 induction is coupled to BECN1 upregulation and autophagy induction. Finally, anti-CD3-and PMA-ionomycin-mediated activation of T-cell receptor signaling in peripheral T cells from lymph nodes of healthy mice results in an upregulation of BECN1 expression that can be blocked by the NF-B inhibitor BAY 11-7082. Altogether, these data suggest that autophagy could represent a novel route modulated by p65 to regulate cell survival and control T-cell homeostasis.Normal cellular development and growth depend on a finely tuned balance between protein synthesis and degradation. Eukaryotic cells exploit two major routes for protein degradation: autophagy and the ubiquitin-proteasome system. Autophagy is a highly conserved catabolic process whereby long-lived proteins and organelles are engulfed in double-membrane structures called autophagosomes and targeted to the lysosome for degradation and ATP production (33). Autophagy was first characterized in yeast as a process used by cells to survive metabolic stress (59). Many of the autophagic executor genes (ATGs) have been discovered in yeast, and recently a number of mammalian orthologues have been identified. At the molecular level, the autophagic pathway is well conserved and requires several proteins acting in concert at different stages for proper autophagosome formation. During the first steps of autophagosome formation, BECN1/Atg6 acts in association with PI3KIII/Vps34 as a platform that recruits activators and inhibitors of autophagy in order to finely regulate autophagosome formation (43). Two ubiquitin-like systems are fundamental for autophagosome enlargement and maturation downstream of BECN1. A first ubiquitin-like system is required for the formation of the Atg5-Atg12 complex, which contributes to autophagosomal membrane elongation (30, 39). The second ubiquitin-like system conjugates LC3 protein to phosphoethanolamine, allowing its incorporation into the autophagosomal membrane and subsequent autophagosome formation (56).In mammalian cells, metabolic stress and genotoxic stimuli, including ceramide and tamoxifen treatment, have been shown to trigger both apoptotic cell death and autophagy (51). A number of emerging pieces of evidence point to a prosurvival role for autophagy. Inactivation of the essential autophagy gene BECN1 results in apoptotic cell death in different mode...

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mentioning

confidence: 62%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

235

179

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“…Autophagy was also detected in growth plate, epiphyseal fusion, and osteoarthritis (Shapiro et al, 2008;van den Berg, 2011). Chondrocytes in these areas were under hypoxia, which mediated the evaluation of HIF1a expression, reduced mTOR activities, and then initiated autophagy (Bohensky et al, 2007;Shapiro and Srinivas, 2007). Under these circumstances, autophagy degraded harmful cytosol and organelles to promote the cell survival.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Prior to Chondrocyte Cell Death During the Degeneration of Meckel's Cartilage

Yang

Zhang

Liu

et al. 2012

The Anatomical Record

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The central portion of Meckel's cartilage degenerates almost immediately after birth. Whether autophagy is involved in this process remains unclear. Thus, to explore the role of autophagy during this process, we have detected the expression of autophagy and apoptosis-related markers in embryonic mice. In E15, Beclin1 and LC3 expressions were weak and negative in Meckel's cartilage, respectively. In E16, chondrocytes of the central portion became hypertrophic. Moderate immunoreactivities of Beclin1 and LC3 were observed in prehypertrophic and hypertrophic chondrocytes of the central portion. In E17, the degradation occurred in the central portion and expanded anteriorly and posteriorly. Beclin1 expression was observed in Meckel's cartilage with an increase in the hypertrophic chondrocytes of the central portion. The expression of LC3 was detected specifically in terminally differentiated hypertrophic chondrocytes. The mRNA expressions of LC3 and Beclin1 from E15 to E17 significantly increased. This result is in accord with the histologic findings. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labeling assay and Caspase 3 expression demonstrated that apoptosis was detected in the lateral part of terminal hypertrophic chondrocytes along the degeneration area of Meckel's cartilage. In addition, Bcl2 expression increased significantly from E15 to E17. These results indicate that autophagy is involved in hypertrophic chondrocytes during the degradation of Meckel's cartilage and occurs prior to chondrocyte cell death during this process. Anat Rec,

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“…TNF-α could induce articular chondrocytes death through promoting cell apoptosis and autophagy (30)(31)(32). Several studies also found that cell autophagy had a protective effect on chondrocytes by inhibiting cell death (33,34). Huang et al (35) demonstrated that leptin was implicated in OA pathogenesis though promoting apoptosis and inhibiting autophagy of chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

miR-4262 regulates chondrocyte viability, apoptosis, autophagy by targeting SIRT1 and activating PI3K/AKT/mTOR signaling pathway in rats with osteoarthritis

Sun

Li²,

Wei³

2017

Exp Ther Med

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Abstract. The present study aimed to investigate the effect and underlying mechanism of microRNA (miR)-4262 in the development of osteoarthritis (OA) in rats. Primary chondrocytes were separated from Sprague-Dawley rats and then treated with tumor necrosis factor-α (TNF-α). The level of miR-4262 was detected in TNF-α-treated chondrocytes, and then the miR-4262 or its target gene sirtuin type 1 (SIRT1) level was overexpressed, or knocked down. Furthermore, cell viability, cell apoptosis, cell autophagy and matrix synthesis, as well as the expressions of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway were detected. miR-4262 was significantly overexpressed in TNF-α-treated chondrocytes compared with untreated cells (P<0.05). TNF-α treatment or miR-4262 overexpression significantly decreased cell viability, autophagy-related proteins levels and matrix synthesis-related proteins levels, as well as increased the apoptotic rate in chondrocytes (P<0.05). Overexpression of SIRT1 significantly increased cell viability, autophagy-related proteins levels and matrix synthesis-related proteins levels, as well as decreased the apoptotic rate in TNF-α-treated chondrocytes (P<0.05). In addition, the effects of miR-4262 on cell viability, cell apoptosis, cell autophagy and matrix synthesis were inhibited by SIRT1 (P<0.05). Furthermore, upregulated miR-4262 remarkably increased the expressions of phosphorylated (p)-PI3K, p-AKT and p-mTOR (P<0.05) in TNF-α treated chondrocytes. The present study revealed that the upregulation of miR-4262 may promote the occurrence and development of OA in rats by regulating cell viability, cell apoptosis, cell autophagy, and matrix synthesis. Furthermore, these roles of miR-4262 may be associated with PI3K/AKT/mTOR signaling pathway.

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HIF-1 Regulation of Chondrocyte Apoptosis: Induction of the Autophagic Pathway

Cited by 139 publications

References 21 publications

p65/RelA Modulates BECN1 Transcription and Autophagy

p65/RelA Modulates BECN1 Transcription and Autophagy

Autophagy Prior to Chondrocyte Cell Death During the Degeneration of Meckel's Cartilage

miR-4262 regulates chondrocyte viability, apoptosis, autophagy by targeting SIRT1 and activating PI3K/AKT/mTOR signaling pathway in rats with osteoarthritis

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