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Volume 17, Number 22, Issue of November 15, 1997 pp. 8657-8666

Cloning and Characterization of Murine Glial Cell-Derived Neurotrophic Factor Inducible Transcription Factor (MGIF)

Received March 19, 1997; revised Aug. 21, 1997; accepted Aug. 25, 1997.

Shunsuke Yajima1, Claas-Hinrich Lammers1, Sang-Hyeon Lee1, Yoshinobu Hara2, Keiko Mizuno3, and M. Maral Mouradian1

1 Genetic Pharmacology Unit, Experimental Therapeutics Branch, National Institute of Neurological Diseases and Stroke, 2 Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, and 3 Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, Bethesda, Maryland 20892

The potent neurotrophic factor glial cell-derived neurotrophic factor (GDNF) is a distant member of the transforming growth factor-beta (TGF-beta ) superfamily of proteins. We report a transcription factor that is the first nuclear protein known to be induced by GDNF, thus designated murine GDNF inducible factor (mGIF). The cDNA was cloned in the course of investigating transcription factors that bind to Sp1 consensus sequences, using the in situ filter detection method, and it was found to encode a protein having the same C2-H2 zinc finger motif as Sp1. Sequence analysis indicated that mGIF is homologous to the human TGF-beta inducible early gene (TIEG) and human early growth response gene-alpha (EGR-alpha ). mGIF is widely distributed in the adult mouse with high mRNA levels in kidney, lung, brain, liver, heart, and testis. In the adult brain, mGIF is abundantly expressed in hippocampus, cerebral cortex, cerebellum, and amygdala with lower amounts in striatum, nucleus accumbens, olfactory tubercle, thalamus, and substantia nigra. During development, mGIF mRNA also has a wide distribution, including in cerebral cortex, cerebellar primordium, kidney, intestine, liver, and lung. GDNF induces the expression of mGIF rapidly and transiently both in a neuroblastoma cell line and in primary cultures of rat embryonic cortical neurons. Co-transfection of the Drosophila SL2 cells using mGIF expression plasmid and reporter constructs having Sp1 binding sites indicated that mGIF represses transcription from a TATA-containing as well as from a TATA-less promoter. These observations suggest that the zinc finger transcription factor mGIF could be important in mediating some of the biological effects of GDNF.

Key words: glial cell-derived neurotrophic factor (GDNF); zinc finger; Sp1; transcription; cloning; transforming growth factor-beta (TGF-beta )




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