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Bit-1 mediates integrin-dependent cell survival through activation of the NFkappaB pathway

Genevieve S Griffiths1, Melanie Grundl, Anna Leychenko

  • 1The Center for Cardiovascular Research and Cell and Molecular Biology, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA.

The Journal of Biological Chemistry
|March 9, 2011
PubMed

Insights

Bit-1 protein regulates cell survival by controlling apoptosis in adherent cells. Integrin signaling pathways activate Bit-1, which enhances cell survival by promoting bcl-2 gene transcription and protecting against programmed cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Dysregulated cell death and survival pathways are implicated in cancer development and metastasis.
  • Integrins are key receptors modulating cell survival signals.
  • Bit-1 is an effector of anoikis (programmed cell death upon detachment) and its function is counteracted by integrin-mediated cell attachment.

Purpose of the Study:

  • To investigate the regulation of Bit-1 by integrins in adherent cells.
  • To elucidate the role of Bit-1 in cell survival and apoptosis.
  • To identify the signaling pathways through which Bit-1 influences cell survival.

Main Methods:

  • Knockdown of endogenous Bit-1 in adherent cells.
  • Re-expression of Bit-1.
  • Induction of apoptosis using staurosporine and serum deprivation.
  • Assessment of apoptosis via caspase-3 activation and TUNEL staining.
  • Measurement of phospho-IκB levels and bcl-2 gene transcription.
  • Analysis of signaling pathways involving focal adhesion kinase, PI3K, and AKT.

Main Results:

  • Knockdown of Bit-1 decreased cell survival and increased apoptosis.
  • Re-expression of Bit-1 restored cell survival.
  • Reduction of Bit-1 enhanced staurosporine and serum-deprivation induced apoptosis.
  • Bit-1 expression increased phospho-IκB levels, leading to bcl-2 gene transcription and Bcl-2 protein expression.
  • Bit-1-mediated regulation of bcl-2 was dependent on focal adhesion kinase, PI3K, and AKT signaling.

Conclusions:

  • Bit-1 plays a crucial role in promoting cell survival in adherent cells.
  • Integrin-mediated cell attachment regulates Bit-1 activity.
  • Bit-1 protects cells from apoptosis through a pathway involving IκB, bcl-2 transcription, and downstream signaling kinases.
  • Bit-1 is a key mediator of cell survival signals in cell-extracellular matrix interactions.

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