A zinc-finger protein, PLAGL2, induces the expression of a proapoptotic protein Nip3, leading to cellular apoptosis.

Abstract	Pleomorphic adenomas gene-like 2 (PLAGL2) protein containing seven C(2)H(2) zinc finger motifs exhibits DNA binding and transcriptional activation activity and is expressed in response to hypoxia or iron deficiency. To identify the target genes of PLAGL2, we transfected mouse PLAGL2 cDNA into Balb/c3T3 fibroblasts and neuroblastoma Neuro2a cells. Both cells were induced to undergo apoptosis by the expression of PLAGL2 as judged by assays of TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling), DNA fragmentation, propidium iodide staining, and the binding of annexin V to the cell surface. The treatment of the cells with an iron chelator, desferrioxamine, resulted in the induction of apoptosis with a concomitant accumulation of PLAGL2 in the nucleus. The expression of PLAGL2 in Balb/c3T3 cells led to the mRNA expression of a proapoptotic factor, Nip3, which can dimerize with Bcl-2. Nip3 mRNA was also induced in desferrioxamine-treated cells. Furthermore, the Nip3 promoter containing a hypoxia-responsive element was activated by PLAGL2, independent of hypoxia-inducible factor-1 (HIF-1). The transfection of antisense oligonucleotide to mouse Nip3 mRNA into PLAGL2-expressing cells led to a decrease in apoptotic cells compared with sense oligonucleotide-transfected cells. Despite the activation of DNA-HIF-1 binding activity under hypoxic conditions, neither an accumulation of HIF-1 alpha nor the activation of HIF-1 was observed following the expression of PLAGL2. These results indicate that PLAGL2 is located downstream of HIF-1 and suggest that PLAGL2 functions as a tumor suppressor in association with HIF-1.
Authors	Atsushi Mizutani, Takako Furukawa, Yasushi Adachi, Susumu Ikehara, Shigeru Taketani
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 18 Pg. 15851-8 (May 03 2002) ISSN: 0021-9258 [Print] United States
PMID	11832486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Annexin A5 BNIP3 protein, human BNIP3L protein, human DNA Probes DNA-Binding Proteins Hif1a protein, mouse Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Membrane Proteins Nuclear Proteins Oligodeoxyribonucleotides, Antisense Plagl2 protein, mouse Proto-Oncogene Proteins RNA-Binding Proteins Recombinant Proteins Thionucleotides Trans-Activators Transcription Factors Tumor Suppressor Proteins Deferoxamine
Topics	3T3 Cells Animals Annexin A5 (metabolism) Apoptosis (drug effects, physiology) Cell Hypoxia (physiology) Cell Membrane (metabolism) DNA Probes DNA-Binding Proteins (genetics, metabolism) Deferoxamine (pharmacology) Gene Expression Regulation Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit In Situ Nick-End Labeling Membrane Proteins (genetics) Mice Neuroblastoma Nuclear Proteins (metabolism) Oligodeoxyribonucleotides, Antisense (pharmacology) Promoter Regions, Genetic Proto-Oncogene Proteins RNA-Binding Proteins (genetics, metabolism) Recombinant Proteins (metabolism) Thionucleotides (pharmacology) Trans-Activators (metabolism) Transcription Factors (metabolism) Transcription, Genetic Transfection Tumor Cells, Cultured Tumor Suppressor Proteins Zinc Fingers

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!