The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

Wu, Hongtan; Xiao, Yali; Zhang, Shihao; Ji, Suyuan; Wei, Luyao; Fan, Fuqin; Geng, Jing; Tian, Jing; Sun, Xiulian; Qin, Funiu; Jin, Chang-Nan; Lin, Jiajing; Yin, Zhenyu; Zhang, Ting; Luo, Lianzhong; Li, Yang; Song, Shuai; Lin, Sheng-Cai; Deng, Xianming; Camargo, Fernando D.; Avruch, Joseph; Chen, Lanfen; Zhou, Dawang

doi:10.1016/j.celrep.2013.04.020

Cited by 110 publications

(112 citation statements)

References 52 publications

(67 reference statements)

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“…Notably, Hippo-dependent or -independent mechanisms of Yap1 transcription remain to be identified. Recently, Wu et al demonstrated that the Ets family member GABP binds to the Yap promoter and activates YAP transcription in liver cancer (27). Our results indicate that menin binds to Yap1 promoter loci and upregulates H3K4me3.…”

Section: Discussionsupporting

confidence: 69%

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Zheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Most studies have focused on epigenetic gene-silencing events; therefore, the mechanism that promotes gene activation in HCC is not well established. We identify an epigenetic activation mechanism whereby menin promotes Yes-associated protein (Yap1) transcription, which is associated with a poor prognosis for HCC patients. Substantial overexpression of the menin–mixed-lineage leukemia complex is associated with increased histone 3 lysine 4 trimethylation at certain loci of the tumor promoter in HCC. Heterozygous ablation of multiple endocrine neoplasia type 1 ( Men1) in mice reduces diethylnitrosamine-induced development of HCC. Our findings reveal that menin plays an important epigenetic role in up-regulating Yap1 transcription, leading to liver tumorigenesis.

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Section: Discussionsupporting

confidence: 69%

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Zheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…These findings suggest that YAP activation during the early phase of liver regeneration may be mediated by increased expression secondary to decreased Mst1/2 activation. In addition, our data contradict previous studies that have demonstrated an increase in CTGF transcription (16,19). This discrepancy may be explained by the different experimental models as prior investigations of YAP transcriptional regulation were performed using knockout models of Hippo pathway components (20) or transgenic overexpression of YAP (2), which are fundamentally different than our liver regeneration model.…”

Section: Discussioncontrasting

confidence: 56%

“…Our results demonstrated a decrease in active p-Mst1/2 levels and increase in total YAP levels by 1 day post-PH. Wu et al (16) demonstrated that Mst1/2 activity in the liver regulates YAP mRNA levels. Using a liver-specific Mst1/2 knockout mouse model, they demonstrated that acute inactivation of Mst1/2 resulted in increased YAP mRNA levels and, subsequently, increased YAP protein levels (16).…”

Section: Discussionmentioning

confidence: 99%

“…Wu et al (16) demonstrated that Mst1/2 activity in the liver regulates YAP mRNA levels. Using a liver-specific Mst1/2 knockout mouse model, they demonstrated that acute inactivation of Mst1/2 resulted in increased YAP mRNA levels and, subsequently, increased YAP protein levels (16). These findings suggest that YAP activation during the early phase of liver regeneration may be mediated by increased expression secondary to decreased Mst1/2 activation.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration

Grijalva

Huizenga

Mueller

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liverto-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.liver; regeneration; Hippo signaling pathway; YAP; partial hepatectomy THE LIVER HAS THE REMARKABLE ability to regenerate following hepatocyte loss (8). The endpoint of regeneration is replacement of lost hepatic mass until the near original liver-to-body weight ratio is restored. In clinical practice, this regulation can be observed following liver resection or partial liver transplantation after which the liver grows to reach the optimal liverto-body weight ratio for the individual. In contrast, large size liver grafts tend to atrophy to reach the optimal liver-to-body weight ratio (4, 13). Even though numerous cytokines and growth factors have been shown to play a role in liver regeneration, the exact mechanisms that are responsible for the initiation and termination of liver regeneration are not fully understood.Recent studies have demonstrated that the Hippo signaling pathway plays a role in liver size regulation through regulation of the transcriptional coactivator Yes-associated protein (YAP) (7,20). While activation of the Hippo pathway leads to phosphorylation of YAP (p-YAP) (2, 9, 18) resulting in YAP cytoplasmic retention and degradation, attenuation of Hippo signaling leads to increased YAP nuclear localization and activation of a proliferative, antiapoptotic transcriptional program (2, 7). Deletion of Hippo pathway components in quiescent liver has been demonstrated to result in ...

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“…Gene amplification of the Yap locus has been reported in a wide spectrum of human and murine malignancies 40,41 . We have previously shown that the Ets family transcriptional factor GABP is required for Yap expression 42 . Recently, verteporfin as a small molecule was shown to inhibit TEAD-Yap association and Yapinduced liver overgrowth 43 .…”

mentioning

confidence: 99%

Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis

et al. 2015

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The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

Cited by 110 publications

References 52 publications

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration

Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis

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