The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

Liu, Huan; Jiang, Dean; Chi, Fangtao; Zhao, Bin

doi:10.1007/s13238-012-2919-3

Cited by 59 publications

(52 citation statements)

References 152 publications

(195 reference statements)

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“…Its deregulation is frequently observed in many types of malignancies, suggesting that alterations of this signaling are connected with cancer progression and patient survival (7)(8)(9)21,33,34). The core components of this pathway include MST1/2, SAV1, LATS1/2 and MOB1 proteins (10,12,15).…”

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confidence: 99%

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Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

et al. 2017

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Abstract. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC (70-80%). Yes-associated protein 1 (YAP1) protein is a nuclear effector of the Hippo pathway and acts as a transcriptional co-activator of genes involved in the processes of growth and development of tissues. Hippo signaling, with its key kinases, MST2 and large tumor suppressor kinase 1 (LATS1), plays a significant role in the negative regulation of the amount and activity of YAP1 protein. Components of the Hippo pathway and YAP1 levels are frequently dysregulated in a variety of tumors, suggestive of their possible involvement in carcinogenesis. Our aim was to evaluate gene and protein expression profiles of YAP1, MST2 and LATS1 and the methylation status of MST2 and LATS1 promoters in ccRCC. mRNA levels of MST2, LATS1 and YAP1 genes were assessed in the tumor and matched normal kidney tissues of 86 patients, and in 12 samples of local metastases by quantitative PCR (qPCR). Proteins were semi-quantified in 58 patient samples by western blotting. Hypermethylation of LATS1 and MST2 promoters was measured by methylation-specific high-resolution-melting qPCR. We found that LATS1 promoter hypermethylation, decreased LATS1 mRNA/protein and increased YAP1 mRNA/protein levels in tumor samples were associated with higher TNM and Fuhrman's stages and patient survival. Higher YAP1 mRNA levels were associated with poor outcome (HR=4.03, p=0.036). No changes in MST2 (promoter/ mRNA/protein) were found. We propose that deregulation of LATS1 and YAP1 expression is associated with ccRCC progression and poor patient survival. Measurement of YAP1 mRNA levels in paired tumor-normal kidney tissue samples may serve as a new prognostic factor in ccRCC.

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confidence: 99%

“…Its deregulation is commonly observed in many human cancers, suggesting that alterations of Hippo signaling may be associated with tumor initiation and/or progression (7)(8)(9). The Hippo core cassette is formed by MST2 (serine/threonine kinase 3, STK3) and large tumor suppressor kinase 1 (LATS1) kinases (10).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

et al. 2017

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“…Moreover, it controls tissue homeostasis, organ size and stem cell functions. Its deregulation is frequently observed in many human cancers, suggesting that alterations of Hippo signalling are connected with tumour initiation and/or progression [9][10][11]. Hyperactivation of the Hippo pathway downstream effectors -YAP1 (Yes-associated protein 1) and TAZ (transcriptional co-activator with PDZ binding motif) may contribute to the development of cancer, however, their activation may also play a positive role in stimulating tissue repair and regeneration following injury [12,13].…”

Section: The Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway in colorectal cancer

Wierzbicki

Rybarczyk

2015

Folia Histochem Cytobiol.

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Colorectal cancer (CRC) is one the most frequently diagnosed neoplastic diseases worldwide. Currently, aside from traditional chemotherapy, advanced CRCs are treated with modern drugs targeting cellular components such as epithelial growth factor receptor (EGFR). Since up to 70% of metastasized CRCs are drug resistant, the description of recent progress in cellular homeostasis regulation may shed new light on the development of new molecular targets in cancer treatment. The Hippo pathway has recently become subject of intense investigations since it plays a crucial role in cell proliferation, differentiation, apoptosis and tumourigenesis. Components of the Hippo pathway are deregulated in various human malignancies, and expression levels of its major signal transducers were proposed as prognostic factors in colorectal cancer. In this review we focused on recent data regarding Hippo pathway, its up-stream signals and down-stream effectors. Hippo negatively regulates its major effectors, YAP1 and TAZ kinases, which act as transcriptional co-activators inducing expression of genes involved not only in tissue repair and proliferation but are also oncoproteins involved in tumour development and progression. The deregulation of Hippo pathway components was found in many malignancies. The interactions between Hippo and Wnt/b-catenin signalling, crucial in the maintenance of cell homeostasis, have been described in relation to the control of intestinal stem cell proliferation and CRC development. The recently discovered positive feedback loop between activated YAP1 and increased EGFR/KRAS signalling found in oesophageal, ovarian and hepatocellular cancer has been related to the CRC progression and resistance to EGFR inhibitors during CRC therapy.

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“…Upon stimulation, the Hippo pathway subsequently phosphorylates YAP, and phosphorylated YAP undergoes degradation or interacts with 14-3-3 for its cytoplasmic retention. When dephosphorylated, YAP enters the nucleus and interacts with TEAD family proteins to induce the transcription of genes that regulate diverse cellular processes, including cell survival, proliferation and differentiation (Zhao et al, 2007;Lian et al, 2010;Pan, 2010;Schlegelmilch et al, 2011;Tamm et al, 2011;Liu et al, 2012;Yu and Guan, 2013;Mo et al, 2014;Piccolo et al, 2014;Varelas, 2014;Yao et al, 2014;Ohgushi et al, 2015). Although the function of YAP in regulating the development of multiple organs has been investigated, its role in the developing nervous system is less well studied.…”

Section: Introductionmentioning

confidence: 99%

YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

et al. 2016

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YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yap nestin conditional knockout and Yap GFAP conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.

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The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

Cited by 59 publications

References 152 publications

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

The Hippo pathway in colorectal cancer

YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

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