scholarly journals Notch signaling is necessary for epithelial growth arrest by TGF-β

2007 ◽  
Vol 176 (5) ◽  
pp. 695-707 ◽  
Author(s):  
Hideki Niimi ◽  
Katerina Pardali ◽  
Michael Vanlandewijck ◽  
Carl-Henrik Heldin ◽  
Aristidis Moustakas
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Notch Signaling ◽  
Transforming Growth Factor ◽  
Notch Pathway ◽  
Transforming Growth Factor Β ◽  
Tumor Invasiveness ◽  
Transcriptional Induction ◽  
Notch1 Receptor ◽  
Epithelial Growth

Transforming growth factor β (TGF-β) and Notch act as tumor suppressors by inhibiting epithelial cell proliferation. TGF-β additionally promotes tumor invasiveness and metastasis, whereas Notch supports oncogenic growth. We demonstrate that TGF-β and ectopic Notch1 receptor cooperatively arrest epithelial growth, whereas endogenous Notch signaling was found to be required for TGF-β to elicit cytostasis. Transcriptomic analysis after blocking endogenous Notch signaling uncovered several genes, including Notch pathway components and cell cycle and apoptosis factors, whose regulation by TGF-β requires an active Notch pathway. A prominent gene coregulated by the two pathways is the cell cycle inhibitor p21. Both transcriptional induction of the Notch ligand Jagged1 by TGF-β and endogenous levels of the Notch effector CSL contribute to p21 induction and epithelial cytostasis. Cooperative inhibition of cell proliferation by TGF-β and Notch is lost in human mammary cells in which the p21 gene has been knocked out. We establish an intimate involvement of Notch signaling in the epithelial cytostatic response to TGF-β.

Interaction of the transforming growth factor-β and Notch signaling pathways in the regulation of granulosa cell proliferation

2016 ◽  
Vol 28 (12) ◽  
pp. 1873 ◽  
Author(s):  
Xiao-Feng Sun ◽  
Xing-Hong Sun ◽  
Shun-Feng Cheng ◽  
Jun-Jie Wang ◽  
Yan-Ni Feng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Growth Factor ◽  
Granulosa Cell ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Notch Pathway ◽  
Transforming Growth Factor Β ◽  
Notch Signalling ◽  
Signalling Pathways

The Notch and transforming growth factor (TGF)-β signalling pathways play an important role in granulosa cell proliferation. However, the mechanisms underlying the cross-talk between these two signalling pathways are unknown. Herein we demonstrated a functional synergism between Notch and TGF-β signalling in the regulation of preantral granulosa cell (PAGC) proliferation. Activation of TGF-β signalling increased hairy/enhancer-of-split related with YRPW motif 2 gene (Hey2) expression (one of the target genes of the Notch pathway) in PAGCs, and suppression of TGF-β signalling by Smad3 knockdown reduced Hey2 expression. Inhibition of the proliferation of PAGCs by N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT), an inhibitor of Notch signalling, was rescued by both the addition of ActA and overexpression of Smad3, indicating an interaction between the TGF-β and Notch signalling pathways. Co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assays were performed to identify the point of interaction between the two signalling pathways. CoIP showed direct protein–protein interaction between Smad3 and Notch2 intracellular domain (NICD2), whereas ChIP showed that Smad3 could be recruited to the promoter regions of Notch target genes as a transcription factor. Therefore, the findings of the present study support the idea that nuclear Smad3 protein can integrate with NICD2 to form a complex that acts as a transcription factor to bind specific DNA motifs in Notch target genes, such as Hey1 and Hey2, and thus participates in the transcriptional regulation of Notch target genes, as well as regulation of the proliferation of PAGCs.

scholarly journals Smad7 Regulates Dental Epithelial Proliferation during Tooth Development

2019 ◽  
Vol 98 (12) ◽  
pp. 1376-1385 ◽  
Author(s):  
Z. Liu ◽  
T. Chen ◽  
D. Bai ◽  
W. Tian ◽  
Y. Chen
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Transforming Growth Factor ◽  
Tooth Development ◽  
Tooth Germ ◽  
Transforming Growth Factor Β ◽  
Tooth Size ◽  
Dental Epithelium ◽  
Tooth Morphogenesis

Tooth morphogenesis involves dynamic changes in shape and size as it proceeds through the bud, cap, and bell stages. This process requires exact regulation of cell proliferation and differentiation. Smad7, a general antagonist against transforming growth factor–β (TGF-β) signaling, is necessary for maintaining homeostasis and proper functionality in many organs. While TGF-β signaling is widely involved in tooth morphogenesis, the precise role of Smad7 in tooth development remains unknown. In this study, we showed that Smad7 is expressed in the developing mouse molars with a high level in the dental epithelium but a moderate to weak level in the dental mesenchyme. Smad7 deficiency led to a profound decrease in tooth size primarily due to a severely compromised cell proliferation capability in the dental epithelium. Consistent with the tooth shrinkage phenotype, RNA sequencing (RNA-seq) analysis revealed that Smad7 ablation downregulated genes referred to epithelial cell proliferation and cell cycle G1/S phase transition, whereas the upregulated genes were involved in responding to TGF-β signaling and cell cycle arrest. Among these genes, the expression of Cdkn1a (encoding p21), a negative cell proliferation regulator, was remarkably elevated in parallel with the diminution of Ccnd1 encoding the crucial cell cycle regulator cyclin D1 in the dental epithelium. Meanwhile, the expression level of p-Smad2/3 was ectopically elevated in the developing tooth germ of Smad7 null mice, indicating the hyperactivation of the canonical TGF-β signaling. These effects were reversed by addition of TGF-β signaling inhibitor in cell cultures of Smad7−/− molar tooth germs, with rescued expression of cyclin D1 and cell proliferation rate. In sum, our studies demonstrate that Smad7 functions primarily as a positive regulator of cell proliferation via inhibition of the canonical TGF-β signaling during dental epithelium development and highlight a crucial role for Smad7 in regulating tooth size.

scholarly journals Human myostatin negatively regulates human myoblast growth and differentiation

2011 ◽  
Vol 301 (1) ◽  
pp. C195-C203 ◽  
Author(s):  
Craig McFarlane ◽  
Gu Zi Hui ◽  
Wong Zhi Wei Amanda ◽  
Hiu Yeung Lau ◽  
Sudarsanareddy Lokireddy ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Muscle Growth ◽  
Notch Pathway ◽  
Transforming Growth Factor Β ◽  
Myoblast Differentiation ◽  
Myogenic Regulatory Factor ◽  
Human Myoblast

Myostatin, a member of the transforming growth factor-β superfamily, has been implicated in the potent negative regulation of myogenesis in murine models. However, little is known about the mechanism(s) through which human myostatin negatively regulates human skeletal muscle growth. Using human primary myoblasts and recombinant human myostatin protein, we show here that myostatin blocks human myoblast proliferation by regulating cell cycle progression through targeted upregulation of p21. We further show that myostatin regulates myogenic differentiation through the inhibition of key myogenic regulatory factors including MyoD, via canonical Smad signaling. In addition, we have for the first time demonstrated the capability of myostatin to regulate the Notch signaling pathway during inhibition of human myoblast differentiation. Treatment with myostatin results in the upregulation of Hes1, Hes5, and Hey1 expression during differentiation; moreover, when we interfere with Notch signaling, through treatment with the γ-secretase inhibitor L-685,458, we find enhanced myotube formation despite the presence of excess myostatin. Therefore, blockade of the Notch pathway relieves myostatin repression of differentiation, and myostatin upregulates Notch downstream target genes. Immunoprecipitation studies demonstrate that myostatin treatment of myoblasts results in enhanced association of Notch1-intracellular domain with Smad3, providing an additional mechanism through which myostatin targets and represses the activity of the myogenic regulatory factor MyoD. On the basis of these results, we suggest that myostatin function and mechanism of action are very well conserved between species, and that myostatin regulation of postnatal myogenesis involves interactions with numerous downstream signaling mediators, including the Notch pathway.

scholarly journals The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

1998 ◽  
Vol 9 (6) ◽  
pp. 1449-1463 ◽  
Author(s):  
Gian Maria Fimia ◽  
Vanesa Gottifredi ◽  
Barbara Bellei ◽  
Maria Rosaria Ricciardi ◽  
Agostino Tafuri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Transforming Growth Factor Β ◽  
Large Tumor ◽  
Cycle Progression

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

scholarly journals JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Long ◽  
Xiaobo Wang ◽  
Xianfa Du ◽  
Hehai Pan ◽  
Jianru Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Intervertebral Disc ◽  
Notch Signaling ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Caspase 8 ◽  
Tnf Α ◽  
Intradiscal Injection

Abstract Background Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis. Methods Recombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed. Results Recombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Conclusions The current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.

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