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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
07:42

Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c

Published on: June 29, 2011

C-terminal binding proteins are essential pro-survival factors that undergo caspase-dependent downregulation during

Trisha R Stankiewicz1,2, Emily K Schroeder1, Natalie A Kelsey2

  • 1Research Service, Veterans Affairs Medical Center, Denver, Colorado, 80220, USA.

Molecular and Cellular Neurosciences
|July 18, 2013
PubMed

Insights

C-terminal binding proteins (CtBPs) are crucial for neuronal survival. Their downregulation by caspases, not just the proteasome, contributes to neuronal apoptosis, revealing a new regulatory pathway.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cellular Biology

Background:

  • C-terminal binding proteins (CtBPs) are transcriptional co-repressors.
  • CtBP expression is typically regulated by proteasome-dependent mechanisms.
  • The role of CtBPs in neuronal survival and apoptosis is not well understood.

Purpose of the Study:

  • To investigate the role of CtBPs in neuronal survival.
  • To explore alternative mechanisms regulating CtBP expression during apoptosis.
  • To elucidate the specific pathways involved in CtBP downregulation in neurons.

Main Methods:

  • Induction of apoptosis in cerebellar granule neurons (CGNs) using various stressors.
  • Antisense-mediated downregulation of CtBP1.
  • Inhibition of CtBPs using 4-methylthio-2-oxobutyric acid.
  • Analysis of CtBP expression and degradation pathways (proteasome vs. caspases).
  • Investigation in mouse embryonic stem cells and DGCR8 knockout cells.

Main Results:

  • CtBPs are downregulated in CGNs undergoing apoptosis.
  • Antisense downregulation of CtBP1 or CtBP inhibition induces apoptosis.
  • CtBP downregulation occurs via stimulus-specific mechanisms, involving either proteasomes or caspases.
  • Caspase-dependent CtBP downregulation occurs at a post-transcriptional level, dependent on miRNA processing.
  • CtBP downregulation contributes to neuronal apoptosis by de-repressing pro-apoptotic genes.

Conclusions:

  • CtBPs are essential pro-survival proteins in neurons.
  • Caspase-dependent downregulation of CtBPs represents an alternative regulatory mechanism to the proteasome.
  • This caspase-mediated pathway, involving miRNA processing, plays a significant role in neuronal apoptosis.
  • Understanding CtBP regulation offers insights into preventing neuronal cell death.
Keywords:
4,6-diamidino-2-phenylidole4-methylthio-2-oxobutyric6-OHDA6-hydroxydopamineADAntiB-cell lymphoma-3BKLFBcl-3C-terminal binding proteinC-terminal binding proteins (CtBPs)CCDCGNsCaspase-3ConCtBPDAPIDGCR8DiGeorge critical region 8EPG protein-coupled receptor kinase-interacting protein-z-shortGITz-shortInvKOLToxMEFsMPP(+)MTOBNeuronal apoptosisPARPPBSPCRRNA silencing suppressorRSSSNPSTSTox BToxin BWTactinomycin Dbasic Krüppel-like factorcerebellar granule neuronscharge-coupled devicecontroldCtBPdrosophila CtBPendoporterinverseknockoutlethal toxinmESCsmethyl-4-phenylpyridiniummiRNAmicro RNAmorpholino-antisense oligonucleotidesmouse embryonic stem cellsmurine embryonic fibroblastsphosphate buffer salinepoly-(ADP-ribose) polymerasepolymerase chain reactionrCasp3recombinant caspase-3sodium nitroprussidestaurosporinewild type

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