Abstract 4313: A LIM protein ajuba suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

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YAP Regulates the Expression ofHoxa1andHoxc13in Mouse and Human Oral and Skin Epithelial Tissues

Molecular and Cellular Biology ◽

10.1128/mcb.00765-14 ◽

2015 ◽

Vol 35 (8) ◽

pp. 1449-1461 ◽

Cited By ~ 18

Author(s):

Ming Liu ◽

Shuangyun Zhao ◽

Qingjie Lin ◽

Xiu-Ping Wang

Keyword(s):

Cell Proliferation ◽

Expression Profiles ◽

Tumor Development ◽

Gene Expression Profiles ◽

Tooth Germ ◽

Conditional Knockout ◽

Hippo Signaling ◽

Embryonic Mouse ◽

Downstream Targets ◽

Epithelial Tissues

Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues.Yapdeficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5)Yapconditional knockout andYAPtransgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR andin situhybridization. We found that YAP regulates the expression ofHoxa1andHoxc13in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested thatHoxa1andHoxc13are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulateHoxa1andHoxc13expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans.

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Brahma is essential for Drosophila intestinal stem cell proliferation and regulated by Hippo signaling

eLife ◽

10.7554/elife.00999 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 39

Author(s):

Yunyun Jin ◽

Jinjin Xu ◽

Meng-Xin Yin ◽

Yi Lu ◽

Lianxin Hu ◽

...

Keyword(s):

Cell Proliferation ◽

Chromatin Remodeling ◽

Intestinal Stem Cells ◽

Hippo Signaling ◽

Protein Levels ◽

Chromatin Remodeling Complex ◽

Proliferation And Differentiation ◽

Resistant Form ◽

Specific Manner ◽

Transcriptional Complex

Chromatin remodeling processes are among the most important regulatory mechanisms in controlling cell proliferation and regeneration. Drosophila intestinal stem cells (ISCs) exhibit self-renewal potentials, maintain tissue homeostasis, and serve as an excellent model for studying cell growth and regeneration. In this study, we show that Brahma (Brm) chromatin-remodeling complex is required for ISC proliferation and damage-induced midgut regeneration in a lineage-specific manner. ISCs and enteroblasts exhibit high levels of Brm proteins; and without Brm, ISC proliferation and differentiation are impaired. Importantly, the Brm complex participates in ISC proliferation induced by the Scalloped–Yorkie transcriptional complex and that the Hippo (Hpo) signaling pathway directly restricted ISC proliferation by regulating Brm protein levels by inducing caspase-dependent cleavage of Brm. The cleavage resistant form of Brm protein promoted ISC proliferation. Our findings highlighted the importance of Hpo signaling in regulating epigenetic components such as Brm to control downstream transcription and hence ISC proliferation.

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ACTN1 Supports Tumor Growth by Inhibiting Hippo Signaling in Hepatocellular Carcinoma

10.21203/rs.3.rs-72190/v1 ◽

2020 ◽

Author(s):

Qian Chen ◽

Xiao-Wei Zhou ◽

Ai-Jun Zhang ◽

Kang He

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Tumor Growth ◽

Expression Pattern ◽

Cytoskeletal Proteins ◽

Gene Set Enrichment Analysis ◽

Hippo Signaling ◽

Hcc Cells

Abstract Background: Alpha actinins (ACTNs) are major cytoskeletal proteins and exhibit many non-muscle functions. Emerging evidence have uncovered the regulatory role of ACTNs in tumorigenesis, however, the expression pattern, biological functions, and underlying mechanism of ACTN1 in hepatocellular carcinoma (HCC) remain largely unexplored.Methods: Immunohistochemical analysis of a HCC tissue microarray (n = 157) was performed to determine the expression pattern and prognostic value of ACTN1 in HCC. In vitro loss-of-function study in HCC cells were carried out to investigate ACTN1 knockdown on cell proliferation. In vivo subcutaneous xenograft model and intrahepatic transplantation model were generated to decipher the contribution of ACTN1 in the tumor growth of HCC. Gene set enrichment analysis, quantitative real-time PCR, Co-immunoprecipitation, immunofluorescence and western blotting were performed to identify the underlying molecular mechanism.Results: It was found that ACTN1 was significantly upregulated in HCC tissues and closely related to llpha-fetoprotein level, tumor thrombus, tumor size, TNM stage and patient prognoses. Knockdown of ACTN1 suppressed in vitro cell proliferation and in vivo tumor growth of HCC cells. Mechanistically, knockdown of ACTN1 increased Hippo signaling pathway activity and decrease Rho GTPases activities. Mechanistically, ACTN1 could competitively interact with MOB1 and decrease the phosphorylation of LATS1 and YAP. The growth-promoting effect induced by ACTN1 was significantly abrogated by pharmacological inhibition of YAP with verteporfin or super-TDU.Conclusions: ACTN1 is highly expressed in HCC tissues and acts as a tumor promoter by suppressing Hippo signaling via physical interaction with MOB1. ACTN1 may serve as a potential prognostic marker and therapeutic target for HCC.

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