Publication Date:
2013-07-16
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748152/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748152/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirose, Takashi -- Horvitz, H Robert -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Aug 15;500(7462):354-8. doi: 10.1038/nature12329. Epub 2013 Jul 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23851392" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis/*genetics
;
Base Sequence
;
Caenorhabditis elegans/*genetics/*metabolism
;
Caenorhabditis elegans Proteins/genetics/metabolism
;
Caspases/*metabolism
;
Gene Expression Regulation, Developmental
;
Molecular Sequence Data
;
Protein-Serine-Threonine Kinases/genetics/metabolism
;
Repressor Proteins/genetics/metabolism
;
Sequence Alignment
;
Sp1 Transcription Factor/*genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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