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Author Notes:

Corresponding Author: H-J. Choo, Ph.D.: Emory University, Department of Pharmacology, 1510 Clifton Rd, Room 5024, Atlanta, GA 30322, USA. T: 404-727-3590, FAX: 404-727-0365 ; hchoo2@emory.edu G.K. Pavlath, Ph.D.: Emory University, Department of Pharmacology, 1510 Clifton Rd, Room 5027, Atlanta, GA 30322, USA. T: 404-727-3353, FAX: 404-727-0365 gpavlat@emory.edu

We thank Dr. M. Hall for initial experiments for the project; Dr. J.P. Canner for critical reading of the manuscript; C. Lam for technical assistance; A. Kotlar for technical assistance with bioinformatics analysis; Emory University School of Medicine Core Facility for Flow Cytometry and the Emory Integrated Proteomics Core for experimental assistance.

Subjects:

Research Funding:

This work was supported by National Institute of Health grants AR062483 (GP) and AR067645 (AC).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell & Tissue Engineering
  • Biotechnology & Applied Microbiology
  • Oncology
  • Cell Biology
  • Hematology
  • Nuclear import
  • Importin alpha 5
  • Satellite cells
  • cNLS proteins
  • Karyopherin alpha 1
  • KPNA1
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • SKELETAL-MUSCLE REGENERATION
  • EMBRYONIC STEM-CELLS
  • GENE-EXPRESSION
  • PROTEIN IMPORT
  • BETA-CATENIN
  • PORE COMPLEX
  • SACCHAROMYCES-CEREVISIAE
  • LOCALIZATION SIGNAL
  • FAMILY-MEMBERS

Karyopherin Alpha 1 Regulates Satellite Cell Proliferation and Survival By Modulating Nuclear Import

Journal Title:

STEM CELLS

Volume:

Volume 34, Number 11

Publisher:

, Pages 2784-2797

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Satellite cells are stem cells with an essential role in skeletal muscle repair. Precise regulation of gene expression is critical for proper satellite cell quiescence, proliferation, differentiation and self-renewal. Nuclear proteins required for gene expression are dependent on the nucleocytoplasmic transport machinery to access to nucleus, however little is known about regulation of nuclear transport in satellite cells. The best characterized nuclear import pathway is classical nuclear import which depends on a classical nuclear localization signal (cNLS) in a cargo protein and the heterodimeric import receptors, karyopherin alpha (KPNA) and beta (KPNB). Multiple KPNA1 paralogs exist and can differ in importing specific cNLS proteins required for cell differentiation and function. We show that transcripts for six Kpna paralogs underwent distinct changes in mouse satellite cells during muscle regeneration accompanied by changes in cNLS proteins in nuclei. Depletion of KPNA1, the most dramatically altered KPNA, caused satellite cells in uninjured muscle to prematurely activate, proliferate and undergo apoptosis leading to satellite cell exhaustion with age. Increased proliferation of satellite cells led to enhanced muscle regeneration at early stages of regeneration. In addition, we observed impaired nuclear localization of two key KPNA1 cargo proteins: p27, a cyclin-dependent kinase inhibitor associated with cell cycle control and lymphoid enhancer factor 1, a critical cotranscription factor for β-catenin. These results indicate that regulated nuclear import of proteins by KPNA1 is critical for satellite cell proliferation and survival and establish classical nuclear import as a novel regulatory mechanism for controlling satellite cell fate.

Copyright information:

© 2016 AlphaMed Press

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