High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control

Tang, Daolin; Kang, Rui; Livesey, Kristen M.; Kroemer, Guido; Billiar, Timothy R.; Houten, Bennett Van; Zeh, Herbert J.; Lotze, Michael T.

doi:10.1016/j.cmet.2011.04.008

Cited by 250 publications

(239 citation statements)

References 59 publications

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“…In vivo, targeted deletion of RAGE in the Kras G12D/+ spontaneous KC cancer model decreased Kras-driven autophagy and subsequently mitochondrial STAT3 and ATP production, confirming the interaction between autophagy and STAT3. Interestingly, intracellular HMGB1, the cognate ligand for RAGE, regulates mitochondrial quality via mitophagy (15). Further studies are required to establish the relationship between HMGB1 and RAGE in autophagy-mediated mitochondrial STAT3 activation and their roles within the emergent pancreatic tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is a catabolic pathway used by cells to support metabolism in response to cell stress (9). We have previously demonstrated significant impact of autophagy on mitochondrial synthesis and function (15). Therefore, we next explored the relationship between autophagy and the IL-6/STAT3 signaling pathway.…”

Section: Autophagy Regulates Mitochondrial Localization and Function Ofmentioning

confidence: 99%

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The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Kang

Loux

Tang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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139

135

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Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)-mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6-induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:Kras G12D/+ (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the "autophagic switch," regulating mitochondrial STAT3 signaling.oncogenesis | bioenergetics | inflammation | metabolism | high-mobility group box 1 P ancreatic cancer ranks as the fourth leading cause of cancer death, accounting for 6-7% of all cancer-related deaths in the United States, in 2011 (1). Most pancreatic ductal adenocarcinomas (PDA) are thought to arise from well-defined precursor lesions, termed pancreatic ductal intraepithelial neoplasia (PanIN) (2). Many human PanIN lesions do not progress to invasive carcinomas, so defining the events that drive carcinogenesis in the emergent tumor microenvironment is of critical importance. Studies into human pancreatic carcinogenesis have been greatly facilitated by the development of a genetically engineered mouse model that expresses oncogenic Kras under a pancreatic promoter Pdx1-Cre:Kras G12D/+ (KC) (3). A more detailed understanding of how these pathways accelerate pancreatic carcinogenesis may allow improved therapeutic strategies.The receptor for advanced glycation endproducts (RAGE) is a member of the Ig superfamily. RAGE and its ligands, including high-mobility group box 1 (HMGB1) and S100, are linked to the development and progression of several cancers by facilitating the maintenance of a chronic inflammatory state (4) and/or by promotion of metastases (5). We previously observed that RAGE sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival during chemotherapy and oxidative stress in vivo and in vitro (6, 7). Autophagy is an essential catabolic process by which cells break down old or damaged organelles and proteins (8). Autophagy promotes cell survival and supports metabolism during cell stress (9). Conversely, apoptosis promotes tumor growth early in the development of cancer (10) during periods of inhibition of autophagy with a subsequent switch to suppressed apoptosis, acquired later...

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Section: Discussionmentioning

confidence: 99%

Section: Autophagy Regulates Mitochondrial Localization and Function Ofmentioning

confidence: 99%

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Kang

Loux

Tang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

139

135

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“…35,36 In the cytoplasm, HMGBs bind immunogenic nucleotides and deliver them to the cytosolic nucleic acid sensors retinoic acid-inducible gene I, MDA5, AIM2 and DAI and to the endosome nucleic acid-sensing TLRs (TLR3, TLR7 and TLR9). 7,10 Reports have also highlighted the interactions of HMGB1 with TLR9, retinoic acid-inducible gene I and TIM-3 10,37,38 and the vital role of HMGBs in autophagy regulation, 39 mitochondrial function and morphology [40][41][42] and cell proliferation. [43][44][45] Comparatively, an understanding of HMGBs in the nucleus is limited.…”

Section: Discussionmentioning

confidence: 99%

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Rao

Yang

et al. 2014

Cell Mol Immunol

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High-mobility group box (HMGB) proteins, a family of chromatin-associated nuclear proteins, play amazingly multifaceted roles in the immune system of mammals. Thus far, little is known about the nucleocytoplasmic distribution of HMGBs in teleosts. The present study systematically investigated the dynamic localization of all six HMGB proteins in Ctenopharyngodon idella kidney (CIK) cells. Under basal conditions, all HMGBs exclusively localized to the nucleus. Grass carp reovirus (GCRV), polyinosinic-polycytidylic (poly(I : C)) potassium salt and lipopolysaccharide (LPS) challenge evoked the nuclear export of HMGBs to various degrees: GCRV challenge induced the highest nuclear export of CiHMGB2b, and poly(I : C) and LPS evoked the highest nucleocytoplasmic shuttling of CiHMGB1b. Overall, the nucleocytoplasmic shuttling of CiHMGB2a and CiHMGB3b was rarely induced by these challenges. Dynamic imaging uncovered that the nucleocytoplasmic GCRV-induced relocation of CiHMGB2b occurred in cells undergoing karyotheca rupture, apoptosis or proliferation. Western blot analyses were used to examine HMGB-EGFP fusion proteins in whole cell lysates, cytosol, nuclear fractions and culture medium. Further investigation demonstrated the nuclear retention of N-terminal HMG-boxes and the nucleocytoplasmic distribution of the C-terminal acidic tails. Comparative analyses of the dynamic relocation of full-length, truncated or chimeric HMGBs confirmed that the intramolecular interaction between HMG-boxes and C-tail domains mediated the nucleocytoplasmic translocation of HMGBs. These results not only provide an overall understanding of the subcellular localization of HMGBs, but also reveal the induction mechanism of the nucleocytoplasmic translocation of HMGBs by GCRV challenge, which lays a foundation for further studies on the interactions among pathogens, HMGBs and pattern recognition receptors in the innate immunity of teleosts. Keywords: grass carp (Ctenopharyngodon idella); grass carp reovirus; HMGBs; innate immunity; subcellular localization INTRODUCTION High-mobility group box (HMGB) proteins are abundant non-histone chromatin components implicated in major DNA transactions. In mammals, there are four family members (HMGB1-4), of which HMGB1, 2 and 3 are characterized by two DNA-binding domains (HMG-box A and B) and a Cterminal acidic tail domain and HMGB4 possesses two HMG-boxes but lacks the acidic tail. 1 In some teleosts, such as fugu (Takifugu), medaka (Oryzias latipes), Tetraodon and stickleback, two paralogous genes were detected for HMGB1 and HMGB2 but not for HMGB3. 2 However, in zebrafish (Danio rerio), salmon (Oncorhynchus), carp (Cyprinus carpio) 2 and grass carp (Ctenopharyngodon idella), 3-5 two paralogs are present within each of the HMGB subfamilies (HMGB1,

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“…Cytoplasmic HMGB1 promotes autophagy by binding beclin-1 ( Figure 1D). Nuclear and extracellular HMGB1 have the ability to sustain autophagy by regulating the expression of heat shock protein β1 and binding RAGE, respectively (16,21). In addition, membrane HMGB1 promotes neurite outgrowth and platelet activation ( Figure 1E).…”

Section: Hmgb1 Functionmentioning

confidence: 99%

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

Chen

Hou

Zhang

et al. 2013

Mol Med

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Damage-associated molecular pattern (DAMP) molecules are essential for the initiation of innate inflammatory responses to infection and injury. The prototypic DAMP molecule, high-mobility group box 1 (HMGB1), is an abundant architectural chromosomal protein that has location-specific biological functions: within the nucleus as a DNA chaperone, within the cytosol to sustain autophagy and outside the cell as a DAMP molecule. Recent research indicates that aberrant activation of HMGB1 signaling can promote the onset of inflammatory and autoimmune diseases, raising interest in the development of therapeutic strategies to control their function. The importance of HMGB1 activation in various forms of liver disease in relation to liver damage, steatosis, inflammation, fibrosis, tumorigenesis and regeneration is discussed in this review.

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High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control

Cited by 250 publications

References 59 publications

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

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