Characterization of Hippo Pathway Components by Gene Inactivation

Plouffe, Steven W.; Meng, Zhipeng; Lin, Kai; Lin, Bryan; Hong, Audrey W.; Chun, Justin V.; Guan, Kun‐Liang

doi:10.1016/j.molcel.2016.10.034

Cited by 234 publications

(252 citation statements)

References 45 publications

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“…Pathological Yap activation is involved in the initiation and progression of various cancers, including pancreatic cancer, by promoting programs essential for tumorigenesis, such as proliferation, survival, stemness, epithelial-to-mesenchymal transition and metastasis programs (Yu et al, 2015; Zanconato et al, 2016b). However, while dysregulation of the Hippo pathway is a key event in many tumor types, mutations in Hippo pathway components themselves are rare, and the mechanisms that liberate Yap during tumorigenesis remain incompletely understood, underscoring the critical need to identify upstream regulators of this pathway (Plouffe et al, 2016; Zanconato et al, 2016b). Our results show that mouse tumors harboring complete p53 inactivation display significantly enhanced active nuclear Yap, suggesting that the wild-type p53 is key for negatively regulating Yap activity in PDAC and in other cancers.…”

Section: Discussionmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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SUMMARY The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

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Section: Discussionmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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“…This possibility has not been addressed in the in vitro studies already mentioned (Dethlefsen et al, ; Kim et al, ; Yu et al, ). For instance, whereas Lats1/2 and YAP activity can be directly regulated bypassing Mst1 (Plouffe et al, ; Wang et al, ; Yu et al, ), it is unclear whether activation of the Hippo pathway by β‐adrenoceptor stimulation involves Mst1 in the heart. It is also unknown what are the downstream target genes that are regulated by the β‐adrenoceptor‐Hippo signalling pathway and contribute to the development and worsening of heart disease.…”

Section: Activation Of β‐Adrenoceptors Upregulates Gal‐3 Expression Imentioning

confidence: 99%

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

Zhao

Nguyen

et al. 2019

British J Pharmacology

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Myocardial fibrosis is a key histopathological component that drives the progression of heart disease leading to heart failure and constitutes a therapeutic target. Recent preclinical and clinical studies have implicated galectin‐3 (Gal‐3) as a pro‐fibrotic molecule and a biomarker of heart disease and fibrosis. However, our knowledge is poor on the mechanism(s) that determine the blood level or regulate cardiac expression of Gal‐3. Recent studies have demonstrated that enhanced β‐adrenoceptor activity is a determinant of both circulating concentration and cardiac expression of Gal‐3. Pharmacological or transgenic activation of β‐adrenoceptors leads to increased blood levels of Gal‐3 and up‐regulated cardiac Gal‐3 expression, effect that can be reversed with the use of β‐adrenoceptor antagonists. Conversely, Gal‐3 gene deletion confers protection against isoprenaline‐induced cardiotoxicity and fibrogenesis. At the transcription level, β‐adrenoceptor stimulation activates cardiac mammalian sterile‐20‐like kinase 1, a pivotal kinase of the Hippo signalling pathway, which is associated with Gal‐3 up‐regulation. Recent studies have suggested a role for the β‐adrenoceptor‐Hippo signalling pathway in the regulation of cardiac Gal‐3 expression thereby contributing to the onset and progression of heart disease. This implies a therapeutic potential of the suppression of Gal‐3 expression. In this review, we discuss the effects of β‐adrenoceptor activity on Gal‐3 as a biomarker and causative mediator in the setting of heart disease and point out pivotal knowledge gaps. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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“…A large number of studies have shown increased expression and/or nuclear accumulation of YAP and TAZ in a wide range of cancers, supporting the notion that disruption of Hippo signalling contributes to tumorigenesis . Surprisingly, however, mutations in genes coding for Hippo pathway effectors are infrequent, suggesting that YAP and TAZ expression in cancer cells is often altered via indirect mechanisms.…”

Section: Discussionmentioning

confidence: 93%

“…The study of YAP and TAZ regulation in cancer has therefore expanded beyond the canonical Hippo pathway and its core kinases (MST1/2 and LATS1/2) to include crosstalk with multiple signalling pathways such as MARK, Wnt, TGFβ/BMP, GPCR, PI3K‐mTOR, Notch, Hedgehog, mevalonate, AR and hypoxia signalling. The upstream and downstream regulatory components of the latter pathways can affect YAP and TAZ levels and activity via a number of mechanisms, thereby contributing to cancer progression . Hippo pathway activity can also be altered by other mechanisms in cancer cells, including copy‐number changes, loss of heterozygosity and epigenetic silencing .…”

Section: Discussionmentioning

confidence: 99%

Expression of the Hippo signalling effectors YAP and TAZ in canine mammary gland hyperplasia and malignant transformation of mammary tumours

Rico

Boerboom

Paquet

2018

Vet Comparative Oncology

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Canine mammary tumours (CMTs) are common neoplasms in dogs that feature many of the clinical, genetic and molecular characteristics of human breast cancer. Despite their high metastatic potential, few adjuvant chemotherapeutic treatment options exist for malignant CMTs, and the development of novel, targeted pharmacological approaches will require a better understanding of their pathogenesis. As recent evidence suggests that dysregulated Hippo signalling is involved in the development and progression of breast cancer, we sought to determine if this pathway could also play a role in CMT. The expression of the Hippo signalling effectors YAP and TAZ was analysed by immunoblotting and immunohistochemistry in samples including normal mammary gland, lobular hyperplasia, benign tumours and malignant tumours of all grades. We found a significant increase in TAZ (but not YAP) expression occurred in lobular hyperplasia relative to normal mammary gland, suggesting a role for TAZ in non-neoplastic epithelial proliferation. Nuclear expression of both TAZ and YAP were significantly higher in malignant tumours than in benign ones, suggesting that Hippo dysregulation could play a role in CMT malignant transformation. No differences in YAP or TAZ expression were detected between grades of malignant tumours. Together, our results indicate that alterations in Hippo signalling may play a role in the pathogenesis of CMT, in a manner similar to breast cancer. Hippo pathway components may therefore represent targets for the development of novel chemotherapeutic agents that could be useful for the treatment of both the human and canine diseases.

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Characterization of Hippo Pathway Components by Gene Inactivation

Cited by 234 publications

References 45 publications

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

Expression of the Hippo signalling effectors YAP and TAZ in canine mammary gland hyperplasia and malignant transformation of mammary tumours

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