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FOX proteins as novel negative regulators of lung fibrosis and mitochondrial respiration

Black, Markaisa
http://orcid.org/0000-0001-8901-7789
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530270199796482

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
The forkhead box, Fox, family of transcription factors have diverse functions that contribute to development and disease. The studies within this dissertation focus on two Fox family members, Forkhead box F1 (FOXF1) and Forkhead box M1 (FOXM1), which have roles that are cell type specific and depend upon cellular context. Although Foxf1 and Foxm1 have distinct functions, in these studies both proteins act as inhibitors: Foxf1 as a transcription factor in pulmonary fibrosis described in Part 1 and Foxm1 as a mitochondrial protein partner in mitochondrial respiration described in Part 2. Part 1: Forkhead Box F1 (FOXF1) is a mesenchymal-specific transcription factor essential for lung development and repair. Although FOXF1 is expressed in normal lung fibroblasts, its role in diseases induced by pathogenic myofibroblasts, such as idiopathic pulmonary fibrosis (IPF) are unknown. IPF is characterized by the scarring of the airway due to the accumulation of collagen-secreting myofibroblasts. Effective therapeutics are limited by an incomplete understanding of the molecular mechanisms that regulate myofibroblast functions. The studies described within were conducted to identify novel functions of FOXF1 in fibroblasts and myofibroblasts during the onset and progression of pulmonary fibrosis. Studies of human normal lung and IPF biopsies provide initial evidence that FOXF1 is lost in fibroblasts populations in IPF patients. Using a transgenic mouse model with myofibroblast-specific inactivation of FOXF1, the present study shows that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion, collagen secretion and promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11), which is a critical step for the pro-fibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Therefore, FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts. Targeting FOXF1 and downstream factors that regulate myofibroblast functions could lead to therapeutic approaches in lung fibrosis. Part 2: Forkhead box M1 (FOXM1) transcription factor activates cell cycle genes and is a well described proto-oncogene in human cancers. However, FOXM1 is localized throughout the cytoplasm and the function of FOXM1 independent of gene transcription is unknown. We identified that FOXM1 is present in the mitochondria and contains a putative mitochondrial targeting sequence which controls its translocation to the mitochondria. Localization of FOXM1 to the mitochondria was associated with significantly decreased mitochondrial membrane potential, mitochondrial respiration, and activity of complexes I, II, III and IV of the electron transport chain (ETC). Mass spectrometry analysis identified pentatricopeptide repeat domain protein 1 (PTCD1) as a FOXM1 protein binding partner. PTCD1 is a mitochondrial leucine-specific tRNA binding protein that negatively regulates leucine-rich ETC complex I and IV protein levels. Mitochondrial FOXM1 directly regulates PTCD1 protein levels and decreases mitochondrial leucine tRNA levels. These data suggest that mitochondrial FOXM1 inhibits mitochondrial respiration by stabilizing PTCD1 proteins and downregulating mitochondrial leucine specific tRNAs. Here we define a new paradigm that FOXM1 has a role apart from transcription and is essential for regulation of mitochondrial homeostasis.
Tatiana Kalin, M.D.Ph.D. (Committee Chair)
Zaza A. Khuchua, Ph.D. (Committee Member)
Brian Gebelein, Ph.D. (Committee Member)
Taosheng Huang, M.D. Ph.D. (Committee Member)
Vladimir Kalinichenko, M.D. Ph.D. (Committee Member)
193 p.
Molecular Biology
Forkhead box transcription factors; FOXM1; FOXF1; lung fibrosis; mitochondrial respiration; cadherins

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Citations

  • Black, M. (2018). FOX proteins as novel negative regulators of lung fibrosis and mitochondrial respiration [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530270199796482

    APA Style (7th edition)

  • Black, Markaisa. FOX proteins as novel negative regulators of lung fibrosis and mitochondrial respiration. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530270199796482.

    MLA Style (8th edition)

  • Black, Markaisa. "FOX proteins as novel negative regulators of lung fibrosis and mitochondrial respiration." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530270199796482

    Chicago Manual of Style (17th edition)

ucin1530270199796482
356
© 2018, some rights reserved.Creative Commons License FOX proteins as novel negative regulators of lung fibrosis and mitochondrial respiration by Markaisa Black is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.