Hippo Component TAZ Functions as a Co-repressor and Negatively Regulates ?Np63 Transcription through TEA Domain (TEAD) Transcription Factor.

ABSTRACT: Transcriptional co-activator with a PDZ binding domain (TAZ) is a WW domain-containing transcriptional co-activator and a core component of an emerging Hippo signaling pathway that regulates organ size, tumorigenesis, metastasis, and drug resistance. TAZ regulates these biological functions by up-regulating downstream cellular genes through transactivation of transcription factors such as TEAD and TTF1. To understand the molecular mechanisms underlying TAZ-induced tumorigenesis, we have recently performed a gene expression profile analysis by overexpressing TAZ in mammary cells. In addition to the TAZ-up-regulated genes that were confirmed in our previous studies, we identified a large number of cellular genes that were down-regulated by TAZ. In this study, we have confirmed these down-regulated genes (including cytokines, chemokines, and p53 gene family members) as bona fide downstream transcriptional targets of TAZ. By using human breast and lung epithelial cells, we have further characterized ?Np63, a p53 gene family member, and shown that TAZ suppresses ?Np63 mRNA, protein expression, and promoter activity through interaction with the transcription factor TEAD. We also show that TEAD can inhibit ?Np63 promoter activity and that TAZ can directly interact with ?Np63 promoter-containing TEAD binding sites. Finally, we provide functional evidence that down-regulation of ?Np63 by TAZ may play a role in regulating cell migration. Altogether, this study provides novel evidence that the Hippo component TAZ can function as a co-repressor and regulate biological functions by negatively regulating downstream cellular genes.

SUBMITTER: Valencia-Sama I 

PROVIDER: S-EPMC4505436 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature