Abstract
Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.
Highlights
Transcriptional coactivator with a PDZ-binding motif (TAZ), called WW domain-containing transcriptional regulator 1, has been identified as a 14-3-3 binding phosphoprotein [1]
Since TAZ is known to promote the development and progression of cancer, we investigated whether it affects the transcriptional activity of the tumor suppressor p53. p53-null H1299 cells were co-transfected with p53 and the p53-specific luciferase reporter, p53 responsive elements (p53REs)-Luc, in the absence or presence of TAZ
We found that high density cell culture enhanced the p21 induction upon the actinomycin D (Act D) treatment, which activated the ribosomal stress response to stabilize the p53 protein [31], suggesting that the transcriptional activity of p53 is regulated by the Hippo pathway through TAZ (Supplementary Figure S2)
Summary
Transcriptional coactivator with a PDZ-binding motif (TAZ), called WW domain-containing transcriptional regulator 1, has been identified as a 14-3-3 binding phosphoprotein [1]. TAZ is one of the mammalian orthologs of Yorkie, a transcriptional coactivator of the Hippo pathway of Drosophila. TAZ has been shown to stimulate transcription by interacting with a number of transcription factors [2]. TAZ plays an important role in the regulation of proliferation, differentiation, tissue growth, and organ morphogenesis [3,4]. TAZ activation has been widely observed in human tumors, in which TAZ was found to be essential for cancer development, progression, and metastasis [5]. Many studies reported a correlation between elevated TAZ activation and the incidence of human cancer
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