Ikaros and its interacting partner CtBP target the metalloprotease ADAMTS10 to modulate pituitary cell function.
We have previously described the expression and up-regulation of the C-terminal Binding Protein (CtBP) in response to pituitary hypoxia. This co-repressor interacts with the hematopoietic factor Ikaros to target several components implicated in cellular growth and apoptotic pathways. To identify common transcriptional pituitary targets we performed promoter arrays using Ikaros and CtBP chromatin immunoprecipitated (ChIP) DNA from pituitary AtT20 cells. This approach yielded a finite list of gene targets common to both transcription factors. Of these, the metalloprotease ADAMTS10 emerged as a validated target. We show the ability of Ikaros to bind the ADAMTS10 promoter, influence its transfected activity, and induce endogenous gene expression. ADAMTS10 is expressed in primary pituitary cells and is down-regulated in Ikaros null mice. Further, knockdown of ADAMTS10 in AtT20 cells recapitulates the impact of Ikaros deficiency on POMC/ACTH hormone expression. These results uncover a novel role for the metalloprotease ADAMTS10 in the pituitary. Additionally, they position this metalloprotease as a potential functional integrator of the Ikaros-CtBP chromatin remodeling network.
Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario M5G 2M9, Canada; University Health Network and the Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada.
Zhongyi
Z
Shen
Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario M5G 2M9, Canada; University Health Network and the Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada.
Sylvia L
SL
Asa
Dept. of Medicine, University of Toronto, Toronto, Ontario M5G 2M9, Canada; University Health Network and the Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada. Electronic address: shereen.ezzat@utoronto.ca.
Shereen
S
Ezzat
D000071096:ADAMTS Proteins / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D051379:Mice; D010902:Pituitary Gland / Q000166:cytology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015203:Reproducibility of Results
D004268:DNA-Binding Proteins; D051740:Ikaros Transcription Factor; D000324:Adrenocorticotropic Hormone; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D000071096:ADAMTS Proteins; C000589641:ADAMTS10 protein, mouse
ADAMTS10; CtBP; Hypoxia; Ikaros; Pituitary tumors