RGD Reference Report - Huntingtin inhibits caspase-3 activation. - Rat Genome Database

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Huntingtin inhibits caspase-3 activation.

Authors: Zhang, Y  Leavitt, BR  Van Raamsdonk, JM  Dragatsis, I  Goldowitz, D  MacDonald, ME  Hayden, MR  Friedlander, RM 
Citation: Zhang Y, etal., EMBO J. 2006 Dec 13;25(24):5896-906. Epub 2006 Nov 23.
RGD ID: 6902918
Pubmed: PMID:17124493   (View Abstract at PubMed)
PMCID: PMC1698892   (View Article at PubMed Central)
DOI: DOI:10.1038/sj.emboj.7601445   (Journal Full-text)

Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild-type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase-3 activation, and overexpression of huntingtin resulted in caspase-3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase-3. Interestingly, mutant huntingtin binds active caspase-3 with a lower affinity and lower inhibitory effect on active caspase-3 than does wild-type huntingtin. Although reduction of huntingtin levels resulted in caspase-3 activation in all conditions examined, the cellular response was cell-type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase-3 activity, suggesting a mechanism whereby caspase-mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase-3 activation, resulting in cell dysfunction and cell death.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HttRatnegative regulation of extrinsic apoptotic signaling pathway  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Htt  (huntingtin)


Additional Information