UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Date

1-20-2004

Document Type

Article

Subjects

Animals; Apoptosis; DNA Damage; DNA Repair; Drosophila Proteins; Drosophila melanogaster; Membrane Proteins; Protein-Serine-Threonine Kinases; Radiation, Ionizing; Transcription, Genetic; Tumor Suppressor Protein p53

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member EIGER: Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.

Rights and Permissions

Citation: Mol Cell Biol. 2004 Feb;24(3):1219-31. Link to article on publisher's website

Related Resources

Link to Article in PubMed

PubMed ID

14729967

 
 

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