PACT is a negative regulator of p53 and essential for cell growth and embryonic development

Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression.

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Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis

AJP Cell Physiology ◽

10.1152/ajpcell.00392.2012 ◽

2013 ◽

Vol 304 (10) ◽

pp. C995-C1001 ◽

Cited By ~ 67

Author(s):

Rani Watts ◽

Virginia L. Johnsen ◽

Jane Shearer ◽

Dustin S. Hittel

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Cell Growth ◽

Noncoding Rna ◽

Transforming Growth Factor ◽

Day Treatment ◽

Global Gene Expression ◽

Transforming Growth Factor Β ◽

Negative Regulator ◽

Human Skeletal Muscle Cells

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (−11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G0/G1phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.

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YAP mediates the positive regulation of hnRNPK on the lung adenocarcinoma H1299 cell growth

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz053 ◽

2019 ◽

Vol 51 (7) ◽

pp. 677-687

Author(s):

Lipei Xu ◽

Tingting Zhang ◽

Wensi Huang ◽

Xiaohui Liu ◽

Junlei Lu ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Contact Inhibition ◽

Negative Regulator ◽

Cell Contact ◽

Reporter System ◽

H1299 Cell ◽

Multifunctional Protein

AbstractLung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) accounts for 80%–85% of diagnostic cases. The molecular mechanisms of NSCLC pathogenesis are not well understood. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a multifunctional protein that regulates gene expression and signal transduction and closely associated with tumorigenesis, but its mechanism of action in the pathogenesis of NSCLC is unclear. In this study, we observed that the expression pattern of hnRNPK in H1299 lung adenocarcinoma cells varied depending on the cell density in culture. Moreover, hnRNPK stimulated the ability of proliferation and colony formation of H1299 cells, which is important for the multilayered cell growth in culture. We further investigated whether there is an association between hnRNPK and the elements involved in the cell contact inhibition pathway. By using quantitative reverse transcriptase-polymerase chain reaction assay and a YAP activity reporter system, we found that hnRNPK upregulated the mRNA and protein levels and transcriptional activity of Yes-associated protein 1 (YAP), a master negative regulator of Hippo contact inhibition pathway. Furthermore, YAP knockdown with siRNA abolished the stimulatory effect of hnRNPK on H1299 cell proliferation. These results suggested that YAP could be one of the effectors of hnRNPK. Our data may provide new clues for further understanding the biological functions of hnRNPK, particularly in the context of lung adenocarcinoma oncogenesis.

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Hevin is down-regulated in many cancers and is a negative regulator of cell growth and proliferation

British Journal of Cancer ◽

10.1054/bjoc.1999.1051 ◽

2000 ◽

Vol 82 (6) ◽

pp. 1123-1130 ◽

Cited By ~ 49

Author(s):

A Claeskens ◽

N Ongenae ◽

J M Neefs ◽

P Cheyns ◽

P Kaijen ◽

...

Keyword(s):

Cell Growth ◽

Negative Regulator ◽

Cell Growth And Proliferation

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CEP97 phosphorylation by Dyrk1a is critical for centriole separation during multiciliogenesis

The Journal of Cell Biology ◽

10.1083/jcb.202102110 ◽

2021 ◽

Vol 221 (1) ◽

Author(s):

Moonsup Lee ◽

Kunio Nagashima ◽

Jaeho Yoon ◽

Jian Sun ◽

Ziqiu Wang ◽

...

Keyword(s):

Embryonic Development ◽

Tyrosine Phosphorylation ◽

Primary Cilia ◽

Structural Characteristics ◽

Xenopus Embryo ◽

Negative Regulator ◽

Dual Specificity ◽

Multiciliated Cells ◽

Cilia Formation

Proper cilia formation in multiciliated cells (MCCs) is necessary for appropriate embryonic development and homeostasis. Multicilia share many structural characteristics with monocilia and primary cilia, but there are still significant gaps in our understanding of the regulation of multiciliogenesis. Using the Xenopus embryo, we show that CEP97, which is known as a negative regulator of primary cilia formation, interacts with dual specificity tyrosine phosphorylation regulated kinase 1A (Dyrk1a) to modulate multiciliogenesis. We show that Dyrk1a phosphorylates CEP97, which in turn promotes the recruitment of Polo-like kinase 1 (Plk1), which is a critical regulator of MCC maturation that functions to enhance centriole disengagement in cooperation with the enzyme Separase. Knockdown of either CEP97 or Dyrk1a disrupts cilia formation and centriole disengagement in MCCs, but this defect is rescued by overexpression of Separase. Thus, our study reveals that Dyrk1a and CEP97 coordinate with Plk1 to promote Separase function to properly form multicilia in vertebrate MCCs.

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Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development

Frontiers in Genetics ◽

10.3389/fgene.2021.761418 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sung-Eun Kim ◽

Karla Robles-Lopez ◽

Xuanye Cao ◽

Kristyn Liu ◽

Pooja J. Chothani ◽

...

Keyword(s):

Embryonic Development ◽

Neural Progenitor Cells ◽

Skeletal Development ◽

Specific Role ◽

Negative Regulator ◽

Structural Defects ◽

Shh Signaling ◽

Embryonic Neurogenesis ◽

Signaling Activity

Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.

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C3G (RapGEF1) localizes to the mother centriole and regulates centriole division and primary cilia dynamics

10.1101/575225 ◽

2019 ◽

Author(s):

Sanjeev Chavan Nayak ◽

Vegesna Radha

Keyword(s):

Embryonic Development ◽

Primary Cilia ◽

Negative Regulator ◽

Ciliated Cells ◽

Wild Type ◽

Centrosomal Protein ◽

Over Expression ◽

Cilia Formation ◽

Mother Centriole ◽

Summary Statement

AbstractC3G (RapGEF1), a negative regulator of β-catenin, plays a role in cell differentiation and is essential for early embryonic development in mice. In this study, we identify C3G as a centrosomal protein that regulates centriole division and primary cilia dynamics. C3G is present at the centrosome in interphase as well as mitotic cells, but is absent at the centrioles in differentiated myotubes. It interacts with, and co-localizes with cenexin in the mother centriole. Stable clone of cells depleted of C3G by CRISPR/Cas9 showed reduction in cenexin protein, and presence of supernumerary centrioles. Over-expression of C3G resulted in inhibition of centrosome division in normal and hydroxyurea treated cells. Proportion of ciliated cells is higher, and cilia length longer in C3G knockout cells. C3G inhibits cilia formation and length dependent on its catalytic activity. Unlike wild type cells, C3G depleted cells inefficiently retracted their cilia upon stimulation to reenter the cell cycle, and proliferated slowly, arresting in G1. We conclude that C3G inhibits centriole division and maintains ciliary homeostasis, properties that may be important for its role in embryonic development.Summary statementWe identify C3G as a centrosomal protein and regulator of centriole number, primary cilia length and resorption. These properties are important for its role in embryogenesis, and suggest that mutations in C3G could cause ciliopathies.

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p45NFE2 Is a Negative Regulator of Erythroid Proliferation Which Contributes to the Progression of Friend Virus-Induced Erythroleukemias

Molecular and Cellular Biology ◽

10.1128/mcb.21.1.73-80.2001 ◽

2001 ◽

Vol 21 (1) ◽

pp. 73-80 ◽

Cited By ~ 18

Author(s):

You-Jun Li ◽

Rachel R. Higgins ◽

Brian J. Pak ◽

Ramesh A. Shivdasani ◽

Paul A. Ney ◽

...

Keyword(s):

Cell Growth ◽

Cell Lines ◽

Globin Gene ◽

Negative Regulator ◽

Erythroid Cell ◽

Specific Gene ◽

Globin Genes ◽

Friend Virus ◽

Wild Type

ABSTRACT In previous studies, we identified a common site of retroviral integration designated Fli-2 in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia cell lines. Insertion of F-MuLV at the Fli-2 locus, which was associated with the loss of the second allele, resulted in the inactivation of the erythroid cell- and megakaryocyte-specific genep45 NFE2 . Frequent disruption ofp45 NFE2 due to proviral insertion suggests a role for this transcription factor in the progression of Friend virus-induced erythroleukemias. To assess this possibility, erythroleukemia was induced by F-MuLV inp45 NFE2 mutant mice. Sincep45 NFE2 homozygous mice mostly die at birth, erythroleukemia was induced in +/− and +/+ mice. We demonstrate that +/− mice succumb to the disease moderately but significantly faster than +/+ mice. In addition, the spleens of +/− mice were significantly larger than those of +/+ mice. Of the 37 tumors generated from the +/− and +/+ mice, 10 gave rise to cell lines, all of which were derived from +/− mice. Establishment in culture was associated with the loss of the remaining wild-typep45 NFE2 allele in 9 of 10 of these cell lines. The loss of a functional p45NFE2 in these cell lines was associated with a marked reduction in globin gene expression. Expression of wild-typep45 NFE2 in the nonproducer erythroleukemic cells resulted in reduced cell growth and restored the expression of globin genes. Similarly, the expression ofp45 NFE2 in these cells also slows tumor growth in vivo. These results indicate thatp45 NFE2 functions as an inhibitor of erythroid cell growth and that perturbation of its expression contributes to the progression of Friend erythroleukemia.

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