PMID:21252910

Citation	Rodríguez-Aznar, E and Nieto, MA (2011) Repression of Puma by scratch2 is required for neuronal survival during embryonic development. Cell Death Differ. 18:1196-207
Abstract	Although Snail factors promote cell survival in development and cancer, the tumor-suppressor p53 promotes apoptosis in response to stress. p53 and Snail2 act antagonistically to regulate p53 upregulated modulator of apoptosis (Puma) and cell death in hematopoietic progenitors following DNA damage. Here, we show that this relationship is conserved in the developing nervous system in which Snail genes are excluded from vertebrate neurons and they are substituted by Scratch, a related but independent neural-specific factor. The transcription of scratch2 is induced directly by p53 after DNA damage to repress puma, thereby antagonizing p53-mediated apoptosis. In addition, we show that scratch2 is required for newly differentiated neurons to survive by maintaining Puma levels low during normal embryonic development in the absence of damage. scratch2 knockdown in zebrafish embryos leads to neuronal death through the activation of the intrinsic and extrinsic apoptotic pathways. To compensate for neuronal loss, the proliferation of neuronal precursors increases in scratch2-deficient embryos, reminiscent of the activation of progenitor/stem cell proliferation after damage-induced apoptosis. Our data indicate that the regulatory loop linking p53/Puma with Scratch is active in the vertebrate nervous system, not only controlling cell death in response to damage but also during normal embryonic development.
Links	PubMed PMC3131948 Online version:10.1038/cdd.2010.190
Keywords	Animals; Apoptosis Regulatory Proteins/metabolism; DNA Damage; Embryonic Development; Gene Knockdown Techniques; Nervous System/embryology; Neurons/cytology; Neurons/metabolism; Proto-Oncogene Proteins/metabolism; Transcription Factors/antagonists & inhibitors; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Suppressor Protein p53/antagonists & inhibitors; Tumor Suppressor Protein p53/metabolism; Zebrafish/embryology; Zebrafish/metabolism; Zebrafish Proteins/antagonists & inhibitors; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
DANRE:A4IGB7	involved_in	GO:0043516: regulation of DNA damage response, signal transduction by p53 class mediator	ECO:0000316: genetic interaction evidence used in manual assertion	ZFIN:ZDB-MRPHLNO-070126-7,ZFIN:ZDB-MRPHLNO-110808-4	P		Seeded From UniProt	complete
DANRE:A4IGB7	involved_in	GO:0043523: regulation of neuron apoptotic process	ECO:0000315: mutant phenotype evidence used in manual assertion	ZFIN:ZDB-MRPHLNO-110808-4	P		Seeded From UniProt	complete
DANRE:P53	involved_in	GO:0042771: intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
DANRE:Q6YI50	involved_in	GO:0043516: regulation of DNA damage response, signal transduction by p53 class mediator	ECO:0000316: genetic interaction evidence used in manual assertion	ZFIN:ZDB-MRPHLNO-070126-7,ZFIN:ZDB-MRPHLNO-110808-4	P		Seeded From UniProt	complete
DANRE:Q6YI50	involved_in	GO:0043523: regulation of neuron apoptotic process	ECO:0000315: mutant phenotype evidence used in manual assertion	ZFIN:ZDB-MRPHLNO-110808-4	P		Seeded From UniProt	complete
DANRE:Q6YI50	enables	GO:0000977: RNA polymerase II transcription regulatory region sequence-specific DNA binding	ECO:0000314: direct assay evidence used in manual assertion		F	occurs_at:(SO:0001158)	Seeded From UniProt	complete
DANRE:Q6YI50	enables	GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific	ECO:0000314: direct assay evidence used in manual assertion		F	occurs_at:(SO:0001158)	Seeded From UniProt	complete
DANRE:Q6YI50	located_in	GO:0000785: chromatin	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
DANRE:Q6YI50	enables	GO:0070888: E-box binding	ECO:0000314: direct assay evidence used in manual assertion		F	occurs_at:(SO:0001158)	Seeded From UniProt	complete
DANRE:Q6YI50	involved_in	GO:1902166: negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	ECO:0000305: curator inference used in manual assertion	GO:0043516	P		Seeded From UniProt	complete
DANRE:Q6YI50	involved_in	GO:1902042: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
DANRE:Q6YI50	involved_in	GO:0000122: negative regulation of transcription by RNA polymerase II	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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