RRC ID 30646
Author Hirose T, Horvitz HR.
Title An Sp1 transcription factor coordinates caspase-dependent and -independent apoptotic pathways.
Journal Nature
Abstract During animal development, the proper regulation of apoptosis requires the precise spatial and temporal execution of cell-death programs, which can include both caspase-dependent and caspase-independent pathways. Although the mechanisms of caspase-dependent and -independent cell killing have been examined extensively, how these pathways are coordinated within a single cell that is fated to die is unknown. Here we show that the Caenorhabditis elegans Sp1 transcription factor SPTF-3 specifies the programmed cell deaths of at least two cells-the sisters of the pharyngeal M4 motor neuron and the AQR sensory neuron-by transcriptionally activating both caspase-dependent and -independent apoptotic pathways. SPTF-3 directly drives the transcription of the gene egl-1, which encodes a BH3-only protein that promotes apoptosis through the activation of the CED-3 caspase. In addition, SPTF-3 directly drives the transcription of the AMP-activated protein kinase-related gene pig-1, which encodes a protein kinase and functions in apoptosis of the M4 sister and AQR sister independently of the pathway that activates CED-3 (refs 4, 5). Thus, a single transcription factor controls two distinct cell-killing programs that act in parallel to drive apoptosis. Our findings reveal a bivalent regulatory node for caspase-dependent and -independent pathways in the regulation of cell-type-specific apoptosis. We propose that such nodes might act as features of a general mechanism for regulating cell-type-specific apoptosis and could be therapeutic targets for diseases involving the dysregulation of apoptosis through multiple cell-killing mechanisms.
Volume 500(7462)
Pages 354-8
Published 2013-8-15
DOI 10.1038/nature12329
PII nature12329
PMID 23851392
PMC PMC3748152
MeSH Animals Apoptosis / genetics* Base Sequence Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Caspases / metabolism* Gene Expression Regulation, Developmental Molecular Sequence Data Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism Repressor Proteins / genetics Repressor Proteins / metabolism Sequence Alignment Sp1 Transcription Factor / genetics* Sp1 Transcription Factor / metabolism*
IF 41.577
Times Cited 25
C.elegans tm607