ROLE OF INTRACELLULAR CALCIUM IN GLUCOCORTICOID-EVOKED LYMPHOID CELL APOPTOSIS

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ROLE OF INTRACELLULAR CALCIUM IN
GLUCOCORTICOID-EVOKED LYMPHOID CELL APOPTOSIS
Devin Morris California State University,
Northridge
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Apoptosis
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Physiological roles of apoptosis

• Development
• Homeostasis
• Disease

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Glucocorticoid Pathway
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Susceptibility of CEM Cell Clones to GC-Evoked
Apoptosis
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GC-induced Increase in Intracellular Calcium in
GC-Susceptible CEM cells
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Time- GC-Dose-Dependent Increase in Ca2i in
CEM-C7-14 Cells
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Modulators of Ca2i Levels Influence GC-Evoked
Death of CEM Cells
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EGTA Suppresses GC-Evoked Increase in Ca2i
Levels in CEM-C7-14 Cells
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Glucocorticoid Signaling Pathway
Pathway Inhibitors
Normal Pathway
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Inhibition of Calmodulin Protects CEM-C7-14 Cells
from GC-evoked Death
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Inhibition of Calmodulin Kinase II Protects
CEM-C7-14 Cells from GC-evoked Death
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Inhibition of Calcineurin Protects CEM-C7-14
Cells from GC-evoked Death
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Conclusions

• GCs increase Ca2i levels only in the
  GC-susceptible CEM-C7-14 cell line in a dose
  dependent manner not in the GC-resistant sister
  cell line, CEM-C1-15.
• Calcium chelation by either BAPTA or EGTA
  protected CEM-C7-14 cells from GC-evoked
  apoptosis, in conjunction with a reduction in the
  amount of free Ca2i.
• The calcium ionophore A23187 causes sensitization
  of CEM-C1-15 cells to GC-evoked apoptosis.
• Inhibition of calmodulin, calmodulin kinase II or
  calcineurin, all intermediates in the calcium
  signaling pathway, impart varying degrees of
  protection to CEM-C7-14 cells from GC-evoked
  apoptosis.
• Our data demonstrate a clear correlation between
  calcium signaling and GC-evoked apoptosis

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Future Goals

• Further studies will aim to understand
  Ca2-dependent changes in gene regulation that
  contribute to apoptosis. Candidate genes such as
  the transcriptional repressor E4BP4, and its
  downstream targets are being studied.
• Our ultimate goal is to understand the molecular
  pathway for apoptosis in T-lymphoid cells as well
  as in other physiologically relevant models for
  apoptosis, such as osteoblasts, keratinocytes and
  macrophages.

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Acknowledgements

• Funded by grants from the NIH MBRS-SCORE Program,
  the CSUN Office of Graduate Studies, Research and
  International Programs, and the CSUN College of
  Science Mathematics.
• Dr. Rheem Medh
• Saul Priceman
• Dr. Carol Shubin
• NASA CSUN/JPL Pair Program