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A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

Cell Rep. 2017 Jul 11;20(2):411-426
Valeria Amodeo 1 , Deli A 1 , Joanne Betts 1 , Stefano Bartesaghi 1 , Ying Zhang 2 , Angela Richard-Londt 2 , Matthew Ellis 2 , Rozita Roshani 1 , Mikaella Vouri 1 , Sara Galavotti 1 , Sarah Oberndorfer 1 , Ana Paula Leite 1 , Alan Mackay 3 , Aikaterini Lampada 1 , Eva Wessel Stratford 4 , Ningning Li 2 , David Dinsdale 5 , David Grimwade 6 , Chris Jones 3 , Pierluigi Nicotera 7 , David Michod 8 , Sebastian Brandner 2 , Paolo Salomoni 9
Valeria Amodeo 1 , Deli A 1 , Joanne Betts 1 , Stefano Bartesaghi 1 , Ying Zhang 2 , Angela Richard-Londt 2 , Matthew Ellis 2 , Rozita Roshani 1 , Mikaella Vouri 1 , Sara Galavotti 1 , Sarah Oberndorfer 1 , Ana Paula Leite 1 , Alan Mackay 3 , Aikaterini Lampada 1 , Eva Wessel Stratford 4 , Ningning Li 2 , David Dinsdale 5 , David Grimwade 6 , Chris Jones 3 , Pierluigi Nicotera 7 , David Michod 8 , Sebastian Brandner 2 , Paolo Salomoni 9
+ et al

[No authors listed]

Author information
  • 1 UCL Cancer Institute, London, WC1E 6DD, UK; Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK.
  • 2 UCL Institute of Neurology, London, WC1N 3BG, UK.
  • 3 Institute of Cancer Research, Sutton, London SM2 5NG, UK.
  • 4 The Norwegian Radium Hospital, Oslo 0379, Norway.
  • 5 MRC Toxicology Unit, Leicester LE1 7HB, UK.
  • 6 Guy's Hospital, King's College London, London SE1 9RT, UK.
  • 7 German Centre for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany.
  • 8 UCL Cancer Institute, London, WC1E 6DD, UK; Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK; UCL Institute of Child Health, London WC1N 1EH, UK.
  • 9 UCL Cancer Institute, London, WC1E 6DD, UK; Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK. Electronic address: p.salomoni@ucl.ac.uk.

摘要


Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells.

KEYWORDS: PML, Polycomb, Slit, cell migration, glioblastoma, neurogenesis, nuclear lamina