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Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors

Isharat Yusuf1, Xiaocui Zhu, Michael G Kharas

  • 1Department of Molecular Biology and Biochemistry, University of California, Irvine, 92697-3900, USA.

Blood
|April 8, 2004
PubMed

Insights

Forkhead Box, class O (FOXO) transcription factors regulate cell cycles. This study shows B-cell receptor signaling inactivates FOXO proteins via PI3K/Akt, crucial for B-cell proliferation and survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Forkhead Box, class O (FOXO) transcription factors regulate cell cycle arrest and apoptosis.
  • Mitogenic stimuli activate phosphoinositide 3-kinase (PI3K)/Akt pathways, inactivating FOXO proteins.
  • The role of PI3K-dependent FOXO inactivation in B-lymphocyte proliferation and survival is unclear.

Purpose of the Study:

  • To investigate the importance of PI3K-dependent FOXO inactivation in B-cell cycle progression and survival.
  • To determine if B-cell receptor (BCR) engagement impacts FOXO function through PI3K signaling.

Main Methods:

  • Studied B-cell receptor (BCR) engagement in primary B cells.
  • Investigated PI3K-dependent phosphorylation and nuclear export of FOXO1.
  • Utilized forced expression of PI3K-independent FOXO variants (FOXO1, FOXO3a) in activated B cells.

Main Results:

  • BCR engagement induces PI3K-dependent phosphorylation and nuclear export of FOXO1 in B cells.
  • Forced expression of PI3K-independent FOXO1 or FOXO3a caused G1 cell-cycle arrest.
  • Forced expression of PI3K-independent FOXO variants increased apoptosis in activated B cells.

Conclusions:

  • FOXO inactivation is a critical outcome of PI3K signaling in primary B cells.
  • PI3K-dependent FOXO inactivation is essential for B-lymphocyte cell-cycle progression and survival.

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