scholarly journals Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 171
Author(s):  
Chiharu Miyajima ◽  
Yuki Kawarada ◽  
Yasumichi Inoue ◽  
Chiaki Suzuki ◽  
Kana Mitamura ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cellular Senescence ◽  
Hippo Pathway ◽  
Physiological Role ◽  
Underlying Mechanism ◽  
Binding Motif ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Tumor Suppressor P53

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.

scholarly journals RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ying-Ying Liang ◽  
Xu-Bin Deng ◽  
Xian-Tao Lin ◽  
Li-Li Jiang ◽  
Xiao-Ting Huang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Actin Remodeling ◽  
Aggressive Tumor ◽  
Subunit B

Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

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.

scholarly journals DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3175
Author(s):  
Katsuhiko Itoh ◽  
Takahiro Ebata ◽  
Hiroaki Hirata ◽  
Takeru Torii ◽  
Wataru Sugimoto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Suppressor ◽  
Dependent Manner ◽  
Tumor Suppressor P53 ◽  
P53 Family ◽  
Gene Encoding ◽  
Myotonic Dystrophy Protein Kinase ◽  
Induced Apoptosis ◽  
Actomyosin Contraction

Tumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regulates actomyosin contraction in response to DNA-damaging agents. To identify a novel p53 regulating gene encoding the modulator of myosin, we conducted DNA microarray analysis. We found that, in response to DNA-damaging agent doxorubicin, expression of myotonic dystrophy protein kinase (DMPK), which is known to upregulate actomyosin contraction, was increased in a p53-dependent manner. The promoter region of DMPK gene contained potential p53-binding sequences and its promoter activity was increased by overexpression of the p53 family protein p73, but, unexpectedly, not of p53. Furthermore, we found that doxorubicin treatment induced p73 expression, which was significantly attenuated by downregulation of p53. These data suggest that p53 induces expression of DMPK through upregulating p73 expression. Overexpression of DMPK promotes contraction of the actomyosin cortex, which leads to formation of membrane blebs, loss of cell adhesion, and concomitant caspase activation. Taken together, our results suggest the existence of p53-p73-DMPK axis which mediates DNA-damage induced actomyosin contraction at the cortex and concomitant cell death.

scholarly journals RBP1 Recruits Both Histone Deacetylase-Dependent and -Independent Repression Activities to Retinoblastoma Family Proteins

1999 ◽  
Vol 19 (10) ◽  
pp. 6632-6641 ◽  
Author(s):  
Albert Lai ◽  
Joseph M. Lee ◽  
Wen-Ming Yang ◽  
James A. DeCaprio ◽  
William G. Kaelin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Histone Deacetylase ◽  
Binding Protein ◽  
Family Members ◽  
The Other ◽  
Dependent Manner ◽  
Block Cell Proliferation

ABSTRACT Retinoblastoma (RB) tumor suppressor family proteins block cell proliferation in part by repressing certain E2F-specific promoters. Both histone deacetylase (HDAC)-dependent and -independent repression activities are associated with the RB “pocket.” The mechanism by which these two repression functions occupy the pocket is unknown. A known RB-binding protein, RBP1, was previously found by our group to be an active corepressor which, if overexpressed, represses E2F-mediated transcription via its association with the pocket. We show here that RBP1 contains two repression domains, one of which binds all three known HDACs and represses them in an HDAC-dependent manner while the other domain functions independently of the HDACs. Thus, RB family members repress transcription by recruiting RBP1 to the pocket. RBP1, in turn, serves as a bridging molecule to recruit HDACs and, in addition, provides a second HDAC-independent repression function.

scholarly journals miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP+-Intoxicated SH-SY5Y Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Jianlei Zhang ◽  
Wei Liu ◽  
Yabo Wang ◽  
Shengnan Zhao ◽  
Na Chang
Keyword(s):  
Cell Proliferation ◽  
Glycogen Synthase ◽  
Underlying Mechanism ◽  
Protective Role ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Protective Effects ◽  
Inflammatory Cytokine Production ◽  
Protein Levels

miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson’s disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP+-intoxicated SH-SY5Y cells in a dose- and time-dependent manner. MTT, TUNEL, and ELISA assays revealed that miR-135b overexpression significantly promoted cell proliferation and inhibited apoptosis and production of TNF-α and IL-1β in SH-SY5Y cells in the presence of MPP+. Luciferase reporter assay demonstrated that GSK3β was a direct target of miR-135b. Moreover, sodium nitroprusside (SNP), a GSK3β activator, dramatically reversed the effects of miR-135b upregulation on cell proliferation, apoptosis, and inflammatory cytokine production in MPP+-intoxicated SH-SY5Y cells. Taken together, miR-135b exerts a protective role via promotion of proliferation and suppression of apoptosis and neuroinflammation by targeting GSK3β in MPP+-intoxicated SH-SY5Y cells, providing a potential therapeutic target for the treatment of PD.

scholarly journals Hippo Pathway-related Genes Expression Is Deregulated in Myeloproliferative Neoplasms

2021 ◽  
Author(s):  
Maira da Costa Cacemiro ◽  
Juçara Gastaldi Cominal ◽  
Luiz Miguel Pereira ◽  
Maria Gabriela Berzoti-Coelho ◽  
Giovana Michelassi Berbel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Hippo Pathway ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Hippo Signaling ◽  
Apoptosis Resistance ◽  
Hematological Disorders

Abstract Myeloproliferative neoplasms (MPN) are hematological disorders characterized by increased proliferation of precursor and mature myeloid cells. MPN patients may present driver mutations in JAK2, MPL, and CALR genes, which are essential to describe the molecular mechanisms of MPN pathogenesis. Despite all the new knowledge on MPN pathogenesis, many questions remain to be answered to develop effective therapies to cure MPN or impair its progression to acute myeloid leukemia. The present study examined the expression levels of the Hippo signaling pathway members in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as the role that they play in disease pathogenesis. The Hippo pathway is a tumor suppressor pathway that participates in the regulation of cell proliferation, differentiation, and death. Our main findings were: (i) expression of tumor suppressor genes from Hippo pathway were downregulated and seemed to be associated with cell resistance to apoptosis and increased proliferation rate; and (ii) Hippo pathway-related gene expression was associated with mutation status in ET and PMF patients. Therefore, the decreased expression of Hippo pathway-related genes may contribute to the malignant phenotype, apoptosis resistance, and cell proliferation in MPN pathogenesis.

Inhibition of cell proliferation by lenalidomide is associated with stimulation of Egr1 transcriptional activity in a chromosome 5 deleted Burkitt’s lymphoma and multiple myeloma cell line

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8110-8110 ◽  
Author(s):  
A. K. Gandhi ◽  
J. Kang ◽  
D. Verhelle ◽  
D. I. Stirling ◽  
P. H. Schafer
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Line ◽  
Transcriptional Activity ◽  
Nuclear Transport ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Chromosome 5

8110 Background: The mechanism by which lenalidomide exerts its anti-proliferative effects in deletion 5q MDS clones or MM cells is not yet fully elucidated. Early growth response (Egr1) gene is a tumor suppressor gene located on chromosome 5q31.1 that encodes a transcription factor involved in the regulation of cell proliferation and apoptosis. We hypothesized that lenalidomide may act by enhancing the expression or activity of Egr1 in sensitive hematopoietic tumor cells, especially those with only a single copy of the Egr1 gene. Methods: Transcriptional activity was measured using luciferase reporter plasmids. Gene knockdown and expression studies used siRNA technology and qRT-PCR, respectively. Cell proliferation was measured by 3H-thymidine incorporation. Results: Lenalidomide stimulated the transcriptional activity of Egr1 in the lenalidomide-sensitive chromosome 5 deleted Burkitt's lymphoma Namalwa CSN.70 and in the MM cell line LP-1. Egr1 siRNA Namalwa cells proliferated more than mock controls, indicating that Egr1 functions as a tumor suppressor in Namalwa cells. Lenalidomide had no effect on expression of Egr1, but augmented Egr1 nuclear transport in a dose-dependent manner. Lenalidomide did not affect expression of the Egr1 downstream effector genes ATF3, fibronectin, p53, PTEN, and TGF-β1, while p21 levels increased. However, lenalidomide-induced p21 expression was not affected in Egr1 siRNA Namalwa cells. Interestingly, lenalidomide’s anti-proliferative potency was greater in Egr1 siRNA Namalwa but not in Egr1 siRNA LP-1 cells. Conclusions: Lenalidomide induces nuclear transport and transcriptional activation of the tumor suppressor Egr1, which may contribute to lenalidomide’s anti-proliferative activity in a non-p21 dependent manner. This activity may be related to the levels of Egr1 expression, explaining why del 5q31 myelodysplastic clones are especially sensitive to the cytotoxic effects of lenalidomide. No significant financial relationships to disclose.

The Ubiquitin Ligase COP1 Promotes Glioma Cell Proliferation by Preferentially Downregulating Tumor Suppressor p53

2016 ◽  
Vol 54 (7) ◽  
pp. 5008-5016 ◽  
Author(s):  
Shenshan Zou ◽  
Yufu Zhu ◽  
Bin Wang ◽  
Fengyuan Qian ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
Glioma Cell ◽  
Tumor Suppressor P53 ◽  
Glioma Cell Proliferation

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

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 449 ◽  
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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