DOCSLIB.ORG

The Role of Pgc1a in Cancer Metabolism and Its Therapeutic Implications Zheqiong Tan1,2,3, Xiangjian Luo1,2,3, Lanbo Xiao1,2,3, Min Tang1,2,3, Ann M

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Pgc1a in Cancer Metabolism and Its Therapeutic Implications Zheqiong Tan1,2,3, Xiangjian Luo1,2,3, Lanbo Xiao1,2,3, Min Tang1,2,3, Ann M Published OnlineFirst April 15, 2016; DOI: 10.1158/1535-7163.MCT-15-0621 Review Molecular Cancer Therapeutics The Role of PGC1a in Cancer Metabolism and its Therapeutic Implications Zheqiong Tan1,2,3, Xiangjian Luo1,2,3, Lanbo Xiao1,2,3, Min Tang1,2,3, Ann M. Bode4, Zigang Dong4, and Ya Cao1,2,3 Abstract PGC1a is a transcription factor coactivator that influences a controlled by oncogenes and transcription factors. PGC1a and majority of cellular metabolic pathways. Abnormal expression of these molecules can form signaling axes that include PML/ PGC1a is associated with several chronic diseases and, in recent PGC1a/PPARa, MITF/PGC1a, and PGC1a/ERRa, which are years, it has been shown to be a critical controller of cancer important in regulating metabolic adaptation in specific cancer development. PGC1a acts as a stress sensor in cancer cells and types. Some of these PGC1a-associated pathways are inherently can be activated by nutrient deprivation, oxidative damage, and activated in cancer cells, and others are induced by stress, which chemotherapy. It influences mitochondria respiration, reactive enable cancer cells to acquire resistance against therapy. Notably, oxygen species defense system, and fatty acid metabolism by certain therapeutic-resistant cancer cells are addicted to PGC1a- interacting with specific transcription factors. The characteristic dependent metabolic activities. Suppression of PGC1a expression traits of PGC1a in maintaining metabolic homeostasis promote resensitizes these cells to therapeutic treatments, which implicates cancer cell survival and tumor metastasis in harsh microenviron- PGC1a as a promising target in cancer molecular classification ments. Not only does PGC1a act as a coactivator, but is also itself and therapy. Mol Cancer Ther; 15(5); 1–9. Ó2016 AACR. Introduction mitochondrial oxidative phosphorylation (OxPhos) by coactivat- ing nuclear respiratory factor 1 and estrogen-related receptors (ERR; Metabolic reprogramming is considered to be a hallmark of refs.18, 19). It has been identified to stimulate fatty acid oxidation cancer (1). Glycolysis, mitochondrial respiration, glutaminolysis, (FAO) through interactions with several transcription factors and fatty acid metabolism are important participants in cancer including sirtuin 1 (SIRT1), PPARs, and hepatocyte nuclear factor development (2–6). These processes provide cancer cells with an 4(20–25), and PGC1a also increases autophagy and thermogen- adaptable metabolic feature and afford survival opportunities for esis through transcription factor EB and uncoupling protein-1, cancer cells undergoing stress (7–9). Among the numerous reg- respectively, under stress condition (26–30). In addition, it has ulators or mediators of cancer metabolism, PPARg coactivator-1 been shown to protect cells against oxidative damage through alpha (PGC1a) is emerging as an essential controller of multiple nuclear factor erythroid 2 (Nrf2) and forkhead box O3 (31–33). metabolic pathways (10, 11). In all of these instances, PGC1a functions as a necessary adaptor PGC1a is strongly activated by conditions causing energy lim- for cells to maintain metabolic balance under harsh situations, and itation, including cold, exercise, and fasting, and is particularly it plays a protective role in preventing chronic disease, such as abundant in tissues demanding large energy consumption (12– skeletal muscle atrophy, heart failure, neurodegeneration, obesity, 14). Once activated, PGC1a interacts with several transcription diabetes, and hepatic steatosis, and some of these diseases are factors and affects various biologic activities under normal phys- predisposing factors for cancer initiation (10, 11, 34, 35). Recently, iologic conditions (15). Induced by exercise, PGC1a can promote a several advances have shown that PGC1a expression is tightly functional fiber switch toward more oxidative types in skeletal associated with cancer progression (10, 11). The exceptional ability muscle cells by interacting with muscle-specificmyocyteenhancer of PGC1a in manipulating cellular metabolism enables cancer cells factor 2 family transcription factors (16, 17). PGC1a also facilitates to thrive under a constantly fluctuating energy status, and highlights the importance of PGC1a in effective cancer therapy (36). 1Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China. 2Key Laboratory of Chinese Ministry of Structure and Regulation Mechanism of Education, Central South University, Hunan, China. 3Key Laboratory PGC1a of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China. 4The Hormel Institute, University of Minne- The PGC1a gene is located on chromosome 4 in human and sota, Austin, Minnesota. encodes a protein containing 798 amino acids (29). When acti- Corresponding Author: Ya Cao, Cancer Research Institute, Xiangya School of vated, PGC1a can be recruited as a transcriptional coactivator to Medicine, Central South University, Xiangya Road 110, Changsha 410078, China. subsequently dock or bind with transcription factors or nuclear Phone: 860-731-8480-5448; Fax: 860-731-8447-0589; E-mail: receptors (NR; refs.15, 37). The N-terminal activation domain and [email protected] LXXLL motifs of PGC1a interact with various transcription factors doi: 10.1158/1535-7163.MCT-15-0621 (19, 37, 38). Proteins, such as CREB-binding protein, p300 Ó2016 American Association for Cancer Research. and steroid receptor that acetylate histones, can be sequentially www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst April 15, 2016; DOI: 10.1158/1535-7163.MCT-15-0621 Tan et al. recruited to the PGC1a transcriptional activator complex, to Ectopic expression of PGC1a has been observed in several cancer remodel the chromatin structure and provide optimal biochem- types (50–53), and it is regulated by several oncogenes and sig- ical conditions for target gene transactivation (39). The C terminal naling pathways (Fig. 1; refs.54–57). Similar to its normal phys- of PGC-1a is believed to recruit the thyroid receptor–associated iologic functions, PGC1a primarily regulates mitochondrial respi- protein/vitamin D receptor–interacting protein/mediator com- ration and detoxification of reactive oxygen species (ROS) in cancer plex that facilitates transcription initiation and interferes with cells through specific signaling pathways and transcription factors RNA processing through Ser/Arg-rich or RNA-binding domains (Table 1). In addition, the involvement of PGC1a in regulating (40, 41). FAO and glucose- or glutamine-derived lipogenesis in cancer cells Notably, PGC1a is controlled by several posttranslational has become clearer in recent years (Fig. 2; refs.49, 51, 58). modifications. Because PGC1a is markedly sensitive to cellular energy status, it is tightly regulated by stress sensors such as AMP- MITF/PGC1a Axis in Melanoma activated protein kinase (AMPK) and SIRT1. Both AMPK-medi- Among all its functions, PGC1a-dependent regulation of ated phosphorylation and SIRT1-mediated deacetylation activate OxPhos is best studied in cancer, especially in melanoma. On PGC1a under energy deprivation conditions (42, 43). In addi- the basis of PGC1a expression levels, melanomas have been tion, the p38 MAPK stabilizes the PGC1a protein by increasing its defined into two subsets with different biologic phenotypes phosphorylation state (44). On the other hand, methylation of (53, 59, 60). The PGC1a-positive cells exhibit elevated mitochon- the arginine residues at the C-terminal region by protein arginine drial oxidative metabolism and substantial ROS detoxifying methyltransferase 1 (PRMT1) decreases PGC1a stability whereas capacities. In contrast, the PGC1a-negative cells are dependent phosphorylation of PGC-1a by Akt/protein kinase B and SUMOy- on glycolysis for survival and are more sensitive to ROS-induced lation at the conserved lysine residue 183 attenuate PGC1a apoptosis (53). In this context, PGC1a is transactivated by the activity (44–46). These diverse posttranslational modifications oncogenic melanocyte lineage-specification transcription factor direct PGC1a to different target genes. In addition to posttrans- (MITF), and the PGC1a-negative cells seldom express MITF (57, lational modifications, PGC1a is also influenced by cellular þ 61). These findings indicate that melanomas classified by the calcium (Ca2 ) and cyclic adenosine monophosphate signaling expression of MITF/PGC1a have different metabolic capacities, (47, 48). Notably, some transcription factors coactivated by resulting in distinct destinies following ROS-inducing treatments PGC1a can, in turn, regulate PGC1a, comprising autoregulatory (53, 57). loops that augment target gene transcription (17). The V600E BRAF mutation plays a critical role in melanoma- a genesis by constitutively activating the MAPK signaling pathways PGC1 and Cancer Metabolism (62, 63). Although the BRAF inhibitor, vemurafenib, and the MEK PGC1a has been shown to be a promoter of carcinogenesis in inhibitor, selumetinib, have achieved superior clinical effects to chemical-induced colon and liver carcinoma mouse models (49). treat BRAF V600E–positive individuals, de novo and acquired Figure 1. Regulation mechanisms of PGC1a in cancer. Oncogenes such as MIFT, P53 enhance the transcriptional activity of PGC1a, whereas MYC and HIF suppress it. PGC1a can also be activated by posttranslational modifications. It is deacetylated by PML or SIRT1,
Load more

Recommended publications
  • Cloning of an Alpha-TFEB Fusion in Renal Tumors Harboring the T(6;11)(P21;Q13) Chromosome Translocation
    Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation Ian J. Davis*†, Bae-Li Hsi‡, Jason D. Arroyo*, Sara O. Vargas§, Y. Albert Yeh§, Gabriela Motyckova*, Patricia Valencia*, Antonio R. Perez-Atayde§, Pedram Argani¶, Marc Ladanyiʈ, Jonathan A. Fletcher*‡, and David E. Fisher*†** *Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; Departments of †Medicine and §Pathology, Children’s Hospital Boston, Boston, MA 02115; ‡Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115; ʈDepartment of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021; and ¶Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21287 Communicated by Phillip A. Sharp, Massachusetts Institute of Technology, Cambridge, MA, March 12, 2003 (received for review January 28, 2003) MITF, TFE3, TFEB, and TFEC comprise a transcription factor family Among members of the MiT family, TFE3 has previously been (MiT) that regulates key developmental pathways in several cell implicated in cancer-associated translocations. TFE3 transloca- lineages. Like MYC, MiT members are basic helix-loop-helix-leucine tions occur in distinctive renal carcinomas of childhood and zipper transcription factors. MiT members share virtually perfect young adults and in alveolar soft part sarcoma. In these trans- homology in their DNA binding domains and bind a common DNA locations, the DNA binding domain of TFE3 is fused to various motif. Translocations of TFE3 occur in specific subsets of human N-terminal partners, including PRCC, NonO (p54nrb), PSF, or renal cell carcinomas and in alveolar soft part sarcomas. Although ASPL (15–20). Although the mechanism through which these multiple translocation partners are fused to TFE3, each transloca- fusions contribute to oncogenesis remains unclear, several stud- tion product retains TFE3’s basic helix–loop–helix leucine zipper.
    [Show full text]
  • Autophagy Activation by Transcription Factor EB (TFEB) in Striatum of HD Mice
    Journal of Huntington’s Disease 5 (2016) 249–260 249 DOI 10.3233/JHD-160211 IOS Press Research Report Autophagy Activation by Transcription Factor EB (TFEB) in Striatum of HDQ175/Q7 Mice Petr Vodickaa, Kathryn Chaseb, Maria Iulianoa, Adelaide Tousleya, Dana T. Valentinea, Ellen Sappa, Kimberly B. Kegel-Gleasona, Miguel Sena-Estevesc, Neil Aroninb and Marian DiFigliaa,∗ aDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA bDepartments of Medicine and Cell Biology, University of Massachusetts, Worcester, MA, USA cDepartment of Neurology, Horae Gene Therapy Center, University of Massachusetts Medical School, Albert Sherman Center, Worcester, MA, USA Abstract. Background: Mutant huntingtin (mHTT) is encoded by the Huntington’s disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy. Objective: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels. Methods: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9. The levels of exogenous TFEB were analyzed using qPCR and Western blot. Proteins involved in autophagy, levels of huntingtin, and striatal-enriched proteins were examined using biochemical and/or immunohistochemical methods. Results: In HD mice expressing TFEB-HA, HA immunoreactivity distributed throughout the striatum in neuronal cell bodies and processes and preferentially in neuronal nuclei and overlapped with a loss of DARPP32 immunoreactivity.
    [Show full text]
  • Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes
    Published OnlineFirst June 4, 2014; DOI: 10.1158/1078-0432.CCR-13-3036 Clinical Cancer Biology of Human Tumors Research Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes Gabriel G. Malouf1, Xiaoping Su7, Hui Yao7, Jianjun Gao8, Liangwen Xiong8, Qiuming He8, Eva Comperat 2, Jer ome^ Couturier3, Vincent Molinie4, Bernard Escudier5, Philippe Camparo6, Denaha J. Doss9, Erika J. Thompson9, David Khayat1, Christopher G. Wood10, Willie Yu11, Bin T. Teh11, John Weinstein7, and Nizar M. Tannir8 Abstract Purpose: MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated. Experimental Design: We performed RNA and exome sequencing on an exploratory set of TRCC (n ¼ 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n ¼ 460). Results: Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of MITF, the transforming growth factor b1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA).
    [Show full text]
  • MITF: Master Regulator of Melanocyte Development and Melanoma Oncogene
    Review TRENDS in Molecular Medicine Vol.12 No.9 MITF: master regulator of melanocyte development and melanoma oncogene Carmit Levy, Mehdi Khaled and David E. Fisher Melanoma Program and Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, 44 Binney Street, Boston, MA 02115, USA Microphthalmia-associated transcription factor (MITF) between MITF and TFE3 in the development of the acts as a master regulator of melanocyte development, osteoclast lineage [8]. From these analyses, it seems that function and survival by modulating various differentia- MITF is the only MiT family member that is functionally tion and cell-cycle progression genes. It has been essential for normal melanocytic development. demonstrated that MITF is an amplified oncogene in a MITF is thought to mediate significant differentiation fraction of human melanomas and that it also has an effects of the a-melanocyte-stimulating hormone (a-MSH) oncogenic role in human clear cell sarcoma. However, [9,10] by transcriptionally regulating enzymes that are MITF also modulates the state of melanocyte differentia- essential for melanin production in differentiated melano- tion. Several closely related transcription factors also cytes [11]. Although these data implicate MITF in both the function as translocated oncogenes in various human survival and differentiation of melanocytes, little is known malignancies. These data place MITF between instruct- about the biochemical regulatory pathways that control ing melanocytes towards terminal differentiation and/or MITF in its different roles. pigmentation and, alternatively, promoting malignant behavior. In this review, we survey the roles of MITF as a Transcriptional and post-translational MITF regulation master lineage regulator in melanocyte development The MITF gene has a multi-promoter organization in and its emerging activities in malignancy.
    [Show full text]
  • Mtor-Dependent Phosphorylation Controls TFEB Nuclear Export
    bioRxiv preprint doi: https://doi.org/10.1101/339416; this version posted June 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. mTOR-dependent phosphorylation controls TFEB nuclear export Gennaro Napolitano1,2, Alessandra Esposito1, Heejun Choi3, Valerio Benedetti1, Maria Matarese1, Chiara Di Malta1, Jlenia Monfregola1, Diego Luis Medina1, Jennifer Lippincott-Schwartz3,4 and Andrea Ballabio1,2,5,* 1Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy. 2Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131 Naples, Italy. 3Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA. 4National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD 20892, USA. 5Department of Molecular and Human Genetics and Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA. *Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/339416; this version posted June 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The transcriptional activation of catabolic processes during starvation is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient re-feeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step.
    [Show full text]
  • TFEB Biology and Agonists at a Glance
    cells Review TFEB Biology and Agonists at a Glance Mingyue Chen †, Yashuang Dai †, Siyu Liu, Yuxin Fan, Zongxian Ding and Dan Li * Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310000, China; [email protected] (M.C.); [email protected] (Y.D.); [email protected] (S.L.); [email protected] (Y.F.); [email protected] (Z.D.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Autophagy is a critical regulator of cellular survival, differentiation, development, and homeostasis, dysregulation of which is associated with diverse diseases including cancer and neurode- generative diseases. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy and lysosome, can enhance autophagic and lysosomal biogenesis and function. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of disease models, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. Therefore, TFEB agonists are a promising strategy to ameliorate diseases implicated with autophagy dysfunction. Recently, several TFEB agonists have been identified and preclinical or clinical trials are applied. In this review, we present an overview of the latest research on TFEB biology and TFEB agonists. Keywords: TFEB agonists; autophagy; lysosome; rapamycin; resveratrol Citation: Chen, M.; Dai, Y.; Liu, S.; 1. Introduction Fan, Y.; Ding, Z.; Li, D. TFEB Biology and Agonists at a Glance. Cells 2021, Autophagy occurs in all types of eukaryotic cells, which is a major cellular pathway 10, 333. https://doi.org/10.3390/ for degradation of long-lived proteins and cytoplasmic organelles [1].
    [Show full text]
  • TFEB-Driven Endocytosis Coordinates Mtorc1 Signaling and Autophagy
    TFEB-driven endocytosis coordinates mTORC1 signaling and autophagy Israel C. Nnah1,2, Biao Wang2, Chaitali Saqcena2, Gregory F. Weber2, Edward M. Bonder2, Dustin Bagley3,4, Rossella De Cegli3,4, Gennaro Napolitano3,4, Diego L. Medina3, Andrea Ballabio3, 4, 5 and Radek Dobrowolski1* 1Glenn Biggs Insitute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA. 2 Department of Biological Sciences, Rutgers University, Newark, NJ, USA, 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA. 4 Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, USA. 5 Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy. 6 Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy SUMMARY RESULTS The mechanistic target of rapamycin kinase complex 1 (MTORC1) is a central cellular kinase that integrates major signaling pathways, allowing for regulation of anabolic and catabolic processes including macroautophagy/autophagy and lysosomal biogenesis. Essential to these processes is the regulatory activity of TFEB (transcription factor EB). In a regulatory feedback loop modulating transcriptional levels of RRAG/Rag GTPases, TFEB controls MTORC1 tethering to membranes and induction of anabolic processes upon nutrient replenishment. We now show that TFEB promotes expression of endocytic genes and increases rates of cellular endocytosis during homeostatic baseline and starvation conditions. TFEB-mediated endocytosis drives assembly of the MTORC1-containing nutrient sensing complex through the formation of endosomes that carry the associated proteins RRAGD, the amino acid transporter SLC38A9, and activate AKT/protein kinase B (AKT p-T308). TFEB-induced signaling endosomes en route to lysosomes are induced by amino acid starvation and are required to dissociate TSC2, re-tether and activate MTORC1 on endolysosomal membranes.
    [Show full text]
  • Differential Regulation of Progranulin Derived Granulin Peptides Tingting
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425959; this version posted January 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Differential regulation of progranulin derived granulin peptides Tingting Zhang1, Huan Du1, Mariela Nunez Santos1, Xiaochun Wu1, Thomas Reinheckel2 and Fenghua Hu1# 1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA 2Institute of Molecular Medicine and Cell Research, Medical Faculty and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany *Running Title: Differential regulation of granulin peptides #To whom correspondence should be addressed: Fenghua Hu, 345 Weill Hall, Ithaca, NY 14853, TEL: 607- 2550667, FAX: 607-2555961, Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425959; this version posted January 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are differentially regulated compared to granulins A and B.
    [Show full text]
  • TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia
    RESEARCH ARTICLE TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia Seongseok Yun1, Nicole D. Vincelette1, Xiaoqing Yu2, Gregory W. Watson1, Mario R. Fernandez3, Chunying Yang3, Taro Hitosugi4, Chia-Ho Cheng2, Audrey R. Freischel3, Ling Zhang5, Weimin Li3, Hsinan Hou6, Franz X. Schaub3, Alexis R. Vedder1, Ling Cen2, Kathy L. McGraw1, Jungwon Moon1, Daniel J. Murphy7, Andrea Ballabio8,9,10,11,12, Scott H. Kaufmann4, Anders E. Berglund2, and John L. Cleveland3 Downloaded from https://bloodcancerdiscov.aacrjournals.org by guest on September 23, 2021. Copyright 2020 American Copyright 2021 by AssociationAmerican for Association Cancer Research. for Cancer Research. ABSTRACT MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism, and tumorigenesis. A variety of alterations drive MYC expression in acute myeloid leukemia (AML), and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC- directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy–lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methycytosine. Finally, activating the TFEB–IDH1/IDH2–TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by an MYC–TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML. SIGNIFIcaNCE: Alterations in epigenetic control are a hallmark of AML.
    [Show full text]
  • PPAR-Α Activation Mediates Innate Host Defense Through Induction of TFEB and Lipid Catabolism
    PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism This information is current as Yi Sak Kim, Hye-Mi Lee, Jin Kyung Kim, Chul-Su Yang, of September 28, 2021. Tae Sung Kim, Mingyu Jung, Hyo Sun Jin, Sup Kim, Jichan Jang, Goo Taeg Oh, Jin-Man Kim and Eun-Kyeong Jo J Immunol published online 8 March 2017 http://www.jimmunol.org/content/early/2017/03/08/jimmun ol.1601920 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/03/08/jimmunol.160192 Material 0.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 8, 2017, doi:10.4049/jimmunol.1601920 The Journal of Immunology PPAR-a Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism Yi Sak Kim,*,†,1 Hye-Mi Lee,*,1 Jin Kyung Kim,*,† Chul-Su Yang,‡ Tae Sung Kim,*,† Mingyu Jung,†,x Hyo Sun Jin,* Sup Kim,*,† Jichan Jang,{ Goo Taeg Oh,‖ Jin-Man Kim,†,x and Eun-Kyeong Jo*,† The role of peroxisome proliferator–activated receptor a (PPAR-a) in innate host defense is largely unknown.
    [Show full text]
  • The Mitf/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation Logan Slade and Thomas Pulinilkunnil
    Published OnlineFirst August 29, 2017; DOI: 10.1158/1541-7786.MCR-17-0320 Review Molecular Cancer Research The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation Logan Slade and Thomas Pulinilkunnil Abstract The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of mote tumorigenesis is reviewed. Likewise, the emerging function transcription factors is emerging as global regulators of cancer cell of the Folliculin (FLCN) tumor suppressor in negatively regulat- survival and energy metabolism, both through the promotion of ing the MiT/TFE family and how loss of this pathway promotes lysosomal genes as well as newly characterized targets, such as cancer is examined. Recent reports are also presented that relate to oxidative metabolism and the oxidative stress response. In addi- the role of MiT/TFE–driven lysosomal biogenesis in sustaining tion, MiT/TFE factors can regulate lysosomal signaling, which cancer cell metabolism and signaling in nutrient-limiting condi- includes the mTORC1 and Wnt/b-catenin pathways, which are tions. Finally, a discussion is provided on the future directions and both substantial contributors to oncogenic signaling. This review unanswered questions in the field. In summary, the research describes recent discoveries in MiT/TFE research and how they surrounding the MiT/TFE family indicates that these transcription impact multiple cancer subtypes. Furthermore, the literature factors are promising therapeutic targets and biomarkers for relating to TFE-fusion proteins in cancers and the potential cancers that thrive in stressful niches. Mol Cancer Res; 15(12); mechanisms through which these genomic rearrangements pro- 1637–43. Ó2017 AACR. Introduction Lysosomal Expression and Regulation (CLEAR) elements are recognized by the MITF family, which in turn promotes gene MITF is an evolutionarily conserved transcription factor with transcription (9, 10).
    [Show full text]
  • The Mitf/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation Logan Slade and Thomas Pulinilkunnil
    Published OnlineFirst August 29, 2017; DOI: 10.1158/1541-7786.MCR-17-0320 Review Molecular Cancer Research The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation Logan Slade and Thomas Pulinilkunnil Abstract The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of mote tumorigenesis is reviewed. Likewise, the emerging function transcription factors is emerging as global regulators of cancer cell of the Folliculin (FLCN) tumor suppressor in negatively regulat- survival and energy metabolism, both through the promotion of ing the MiT/TFE family and how loss of this pathway promotes lysosomal genes as well as newly characterized targets, such as cancer is examined. Recent reports are also presented that relate to oxidative metabolism and the oxidative stress response. In addi- the role of MiT/TFE–driven lysosomal biogenesis in sustaining tion, MiT/TFE factors can regulate lysosomal signaling, which cancer cell metabolism and signaling in nutrient-limiting condi- includes the mTORC1 and Wnt/b-catenin pathways, which are tions. Finally, a discussion is provided on the future directions and both substantial contributors to oncogenic signaling. This review unanswered questions in the field. In summary, the research describes recent discoveries in MiT/TFE research and how they surrounding the MiT/TFE family indicates that these transcription impact multiple cancer subtypes. Furthermore, the literature factors are promising therapeutic targets and biomarkers for relating to TFE-fusion proteins in cancers and the potential cancers that thrive in stressful niches. Mol Cancer Res; 1–7. Ó2017 mechanisms through which these genomic rearrangements pro- AACR. Introduction Lysosomal Expression and Regulation (CLEAR) elements are recognized by the MITF family, which in turn promotes gene MITF is an evolutionarily conserved transcription factor with transcription (9, 10).
    [Show full text]