Transcriptional coactivator with PDZ-binding motif stimulates epidermal regeneration via induction of amphiregulin expression after ultraviolet damage

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.

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Transcriptional coactivator PGC-1α contains a novel CBP80-binding motif that orchestrates efficient target gene expression

Genes & Development ◽

10.1101/gad.309773.117 ◽

2018 ◽

Vol 32 (7-8) ◽

pp. 555-567 ◽

Cited By ~ 9

Author(s):

Hana Cho ◽

Xavier Rambout ◽

Michael L. Gleghorn ◽

Phuong Quoc Thuc Nguyen ◽

Christopher R. Phipps ◽

...

Keyword(s):

Gene Expression ◽

Target Gene ◽

Binding Motif ◽

Transcriptional Coactivator ◽

Target Gene Expression

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Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression

Nature Communications ◽

10.1038/s41467-020-19193-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Patricia P. Yee ◽

Yiju Wei ◽

Soo-Yeon Kim ◽

Tong Lu ◽

Stephen Y. Chih ◽

...

Keyword(s):

Tumor Cells ◽

Tumor Necrosis ◽

Feedback Loop ◽

Lipid Peroxides ◽

Binding Motif ◽

Transcriptional Coactivator ◽

Chronic Ischemia ◽

Neutrophil Depletion ◽

Early Tumor

Abstract Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.

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Transcriptional Coactivator with PDZ-binding Motif Is Essential for Normal Alveolarization in Mice

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200812-1827oc ◽

2009 ◽

Vol 180 (4) ◽

pp. 326-338 ◽

Cited By ~ 64

Author(s):

Akihisa Mitani ◽

Takahide Nagase ◽

Kazunori Fukuchi ◽

Hiroyuki Aburatani ◽

Ryosuke Makita ◽

...

Keyword(s):

Binding Motif ◽

Transcriptional Coactivator

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Yap, Taz and Areg Expression in Eighth Cranial Nerve Schwannoma

The International Journal of Biological Markers ◽

10.5301/ijbm.5000263 ◽

2017 ◽

Vol 32 (3) ◽

pp. 319-324 ◽

Cited By ~ 6

Author(s):

Alessandro Martini ◽

Gino Marioni ◽

Elisabetta Zanoletti ◽

Rocco Cappellesso ◽

Roberto Stramare ◽

...

Keyword(s):

Cranial Nerve ◽

Preliminary Investigation ◽

Binding Motif ◽

Transcriptional Coactivator ◽

Eighth Cranial Nerve ◽

Non Invasive ◽

Contrast Enhanced ◽

Direct Target Gene ◽

Direct Target ◽

Cranial Nerve Viii

Background Although the diagnosis and treatment of eighth cranial nerve (VIII CN) schwannoma (acoustic neuroma) has improved over the years, no factors capable of predicting tumor growth have been identified as yet. This study is a preliminary investigation of the expression in sporadic VIII CN schwannomas of Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), and amphiregulin (AREG), a direct target gene of YAP and TAZ. The expression of YAP, TAZ and AREG was correlated with the volumetric dimensions of tumors on contrast-enhanced magnetic resonance imaging (ceMRI). Methods YAP, TAZ and AREG expression was assessed immunohistochemically in surgical specimens of 36 consecutive sporadic VIII CN schwannomas. 3D reconstructions of the tumors and their corresponding volumes in cm3 were obtained from measurements on ceMRI images using the OsiriX® software. Results We found a significant direct correlation between TAZ expression and VIII CN schwannoma volumes on latest preoperative ceMRI (p<0.0003). Mean TAZ expression was also significantly higher in VIII CN schwannomas with a volume ≥2.1 cm3 than in those with a volume <2.1 cm3 (p<0.0018). No significant correlations emerged for YAP or AREG expression and VIII CN schwannoma volume. Conclusions The immunohistochemical expression of TAZ (but not YAP or AREG) correlated significantly with schwannoma volume measured on ceMRI. Further investigations are needed to identify the biological factors influencing tumor proliferation (ideally secreted proteins like AREG) that might be detected using non-invasive approaches (i.e., blood samples).

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Transcriptional Coactivation of Bone-Specific Transcription Factor Cbfa1 by TAZ

Molecular and Cellular Biology ◽

10.1128/mcb.23.3.1004-1013.2003 ◽

2003 ◽

Vol 23 (3) ◽

pp. 1004-1013 ◽

Cited By ~ 131

Author(s):

Cai Bin Cui ◽

Lyndon F. Cooper ◽

Xiangli Yang ◽

Gerard Karsenty ◽

Ikramuddin Aukhil

Keyword(s):

Transcription Factor ◽

Nuclear Localization ◽

Dominant Negative ◽

Specific Gene ◽

Binding Motif ◽

Transcriptional Coactivator ◽

Binding Factor ◽

Osteocalcin Gene ◽

Nih 3T3 ◽

Dose Dependent Increase

ABSTRACT Core-binding factor 1 (Cbfa1; also called Runx2) is a transcription factor belonging to the Runt family of transcription factors that binds to an osteoblast-specific cis-acting element (OSE2) activating the expression of osteocalcin, an osteoblast-specific gene. Using the yeast two-hybrid system, we identified a transcriptional coactivator, TAZ (transcriptional coactivator with PDZ-binding motif), that binds to Cbfa1. A functional relationship between Cbfa1 and TAZ is demonstrated by the coimmunoprecipitation of TAZ by Cbfa1 and by the fact that TAZ induces a dose-dependent increase in the activity of osteocalcin promoter-luciferase constructs by Cbfa1. A dominant-negative construct of TAZ in which the coactivation domains have been deleted reduces osteocalcin gene expression down to basal levels. NIH 3T3, MC 3T3, and ROS 17/2.8 cells showed the expected nuclear localization of Cbfa1, whereas TAZ was distributed throughout the cytoplasm with some nuclear localization when transfected with either Cbfa1 or TAZ. Upon cotransfection by both Cbfa1 and TAZ, the transfected TAZ shows predominant nuclear localization. The dominant-negative construct of TAZ shows minimal nuclear localization upon cotransfection with Cbfa1. These data indicate that TAZ is a transcription coactivator for Cbfa1 and may be involved in the regulation of osteoblast differentiation.

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Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

Cancers ◽

10.3390/cancers10110449 ◽

2018 ◽

Vol 10 (11) ◽

pp. 449 ◽

Cited By ~ 4

Author(s):

Xinyan Ji ◽

Lihua Song ◽

Li Sheng ◽

Anhui Gao ◽

Yang Zhao ◽

...

Keyword(s):

Target Genes ◽

Hippo Pathway ◽

Specific Inhibitor ◽

Drug Candidate ◽

Binding Motif ◽

Mrna Levels ◽

Transcriptional Coactivator ◽

Genetic Inactivation ◽

Liver Enlargement ◽

The Hippo Pathway

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.

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