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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
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Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells

G R Benoit1, M Flexor, F Besançon

  • 1INSERM U-496, Centre G. Hayem Hôpital Saint-Louis 75010 Paris, France.

Molecular Endocrinology (Baltimore, Md.)
|July 4, 2001
PubMed

Insights

Selective rexinoids trigger apoptosis in immature leukemia cells as a default pathway. This programmed cell death is distinct from retinoic acid receptor (RAR) signaling, which promotes differentiation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Retinoid X receptors (RXRs) form heterodimers with retinoic acid receptors (RARs).
  • Selective RXR ligands (rexinoids) were previously considered silent in these heterodimers.
  • No selective rexinoid signaling pathway had been described in cellular systems.

Purpose of the Study:

  • To investigate the signaling capacity of rexinoids independently of RARs.
  • To identify cellular pathways activated by selective rexinoids.
  • To characterize the cellular response to rexinoids in leukemia cells.

Main Methods:

  • Utilized NB4 promyelocytic leukemia cells.
  • Administered selective rexinoid agonists and antagonists.
  • Investigated apoptosis induction and inhibition.
  • Examined the effects of survival signals, RAR agonists, and protein kinase A activation.

Main Results:

  • Rexinoids trigger apoptosis in immature NB4 cells as a default pathway in the absence of survival factors.
  • Rexinoid-induced apoptosis exhibits characteristics of programmed cell death and is inhibited by RXR antagonists.
  • Survival signals, RARalpha agonists, and protein kinase A activation block rexinoid-induced apoptosis.
  • Rexinoid-induced apoptosis is independent of the promyelocytic leukemia-RARalpha fusion protein.

Conclusions:

  • Rexinoids activate a distinct default death pathway in certain leukemia cells.
  • This rexinoid-activated pathway converges with other signaling paradigms.
  • The rexinoid pathway is separate from the RAR agonist pathway that controls cell maturation and postmaturation apoptosis.

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