Ikaros and its interacting partner CtBP target the metalloprotease ADAMTS10 to modulate pituitary cell function

- Ikaros & C-terminal Binding Protein (CtBP) coordinate pituitary response to hypoxia.
- The metalloprotease ADAMTS10 is a target of Ikaros and CtBP in pituitary cells.
- ADAMTS10 is expressed in anterior pituitary cells & diminished in Ikaros-null mice.
- ADAMTS10 modulates proliferation and ACTH secretion in AtT20 pituitary cells.
- ADAMTS10 is a candidate modulator of pituitary growth factor responses to hypoxia.

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.