ANKRD1 acts as a transcriptional repressor of MMP-13 via the AP-1 site.

Molecular and cellular biology

PubMedID: 24515436

Almodóvar-García K, Kwon M, Samaras SE, Davidson JM. ANKRD1 acts as a transcriptional repressor of MMP-13 via the AP-1 site. Mol Cell Biol. 2014;.
The transcriptional co-factor ANKRD1 is sharply induced during wound repair, and its overexpression enhances healing. We recently found that global deletion of murine Ankrd1 impairs wound contraction and enhances necrosis of ischemic wounds. A qPCR array of Ankrd1(-/-) (KO) fibroblasts indicated that ANKRD1 regulates MMP genes. Yeast two-hybrid and co-immunoprecipitation analyses associated ANKRD1 with nucleolin, which represses AP-1 activation of MMP13. Ankrd1 deletion enhanced both basal and PMA-induced MMP13 promoter activity, conversely Ankrd1 overexpression in control cells decreased PMA-induced MMP13 promoter activity. Ankrd1 reconstitution in KO fibroblasts decreased MMP13 mRNA while Ankrd1 knockdown increased these levels. MMP13 mRNA and protein were elevated in intact skin and wounds of KO versus Ankrd1(fl/fl) (FLOX) mice. EMSA gel shift patterns suggested that additional transcription factors bind to the MMP13 AP-1 site in the absence of Ankrd1, and this concept was reinforced by ChIP analysis as greater binding of c-Jun to the AP-1 site in extracts from FLOX vs. KO fibroblasts. We propose that ANKRD1, in association with factors such as nucleolin, represses MMP-13 transcription. Ankrd1 deletion additionally relieved MMP10 transcriptional repression. Nuclear ANKRD1 appears to modulate extracellular matrix remodeling by MMPs.