scholarly journals LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

2019 ◽  
Author(s):  
Dongdong Chen ◽  
Julie Cox ◽  
Jayabhargav Annam ◽  
Melanie Weingart ◽  
Grace Essien ◽  
...  
Keyword(s):  
Rna Binding ◽  
Xenograft Model ◽  
Aurora Kinase ◽  
Serine Threonine Kinase ◽  
Self Renewal ◽  
Threonine Kinase ◽  
Murine Xenograft Model ◽  
Oncogenic Driver ◽  
And Migration ◽  
Cure Rates

ABSTRACTNeuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, opposes the effects of LIN28B. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and self-renewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7 and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B. Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.

scholarly journals Fas-activated serine/threonine kinase (FAST) phosphorylates TIA-1 during Fas-mediated apoptosis.

1995 ◽  
Vol 182 (3) ◽  
pp. 865-874 ◽  
Author(s):  
Q Tian ◽  
J Taupin ◽  
S Elledge ◽  
M Robertson ◽  
P Anderson
Keyword(s):  
Dna Fragmentation ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Jurkat Cells ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Nuclear Rna

We have identified a serine/threonine kinase that is rapidly activated during Fas-mediated apoptosis. Fas-activated serine/threonine kinase (FAST) is phosphorylated on serine and threonine residues in Jurkat cells. In response to Fas ligation, it is rapidly dephosphorylated and concomitantly activated to phosphorylate TIA-1, a nuclear RNA-binding protein that has been implicated as an effector of apoptosis. Phosphorylation of TIA-1 precedes the onset of DNA fragmentation, suggesting a role in signaling downstream events in the apoptotic program. Our results introduce Fast and TIA-1 as components of a molecular cascade involved in signaling Fas-mediated apoptosis.

Regulation of the cytokinesis cleavage furrow by PKCε

2014 ◽  
Vol 42 (6) ◽  
pp. 1534-1537 ◽  
Author(s):  
Nicola Brownlow ◽  
Tanya Pike ◽  
Victoria Crossland ◽  
Jeroen Claus ◽  
Peter Parker
Keyword(s):  
Cell Cycle ◽  
Actin Binding ◽  
Cleavage Furrow ◽  
Binding Region ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Dna Segregation ◽  
Daughter Cells ◽  
Cell Adhesion And Migration ◽  
And Migration

Cytokinesis is the final act of the cell cycle where the replicated DNA and cellular contents are finally split into two daughter cells. This process is very tightly controlled as DNA segregation errors and cytokinesis failure is commonly associated with aneuploidy and aggressive tumours. Protein kinase Cε (PKCε) is a lipid-activated serine/threonine kinase that is part of the PKC superfamily. PKCε plays a complex role in the regulation of migration, adhesion and cytokinesis and in the present article we discuss the interplay between these processes. Integrin-mediated interaction with the actin cytoskeleton is a known regulator of cell adhesion and migration and there is emerging evidence that this pathway may also be essential for cytokinesis. We discuss evidence that a known actin-binding region in PKCε is involved in PKCε-mediated regulation of cytokinesis, providing a link between integrin-mediated stabilization of the cytokinesis furrow and PKCε recruitment.

scholarly journals Pim1 Serine/Threonine Kinase Regulates the Number and Functions of Murine Hematopoietic Stem Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2303-2303
Author(s):  
Ningfei An ◽  
Yingwei Lin ◽  
Sandeep Mahajan ◽  
Yong Wang ◽  
Andrew Kraft ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Cxcr4 Expression ◽  
Cancer Center ◽  
Serine Threonine Kinase ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Threonine Kinase

Abstract Abstract 2303 Background: The genes and pathways that govern the functions and expansion of hematopoietic stem cells (HSC) remain to be elucidated. Pim (proviral insertion in murine lymphomas) protein kinases are a small family of constitutively active, highly conserved oncogenic serine/threonine kinases and have 3 members: Pim1, Pim2, and Pim3. Currently, little is known about the contribution of each Pim kinase in hematopoiesis. Pim1 was recently found to be important in the regulation of CXCR4 expression in HSCs (Grundler R et al, J. Exp Med 2009, 206:1957). However, the roles of Pim1 in HSC proliferation, self-renewal, and long-term repopulation are unclear. In the current study, we performed detailed hematological and bone marrow transplant studies to address these questions. Methods: We generated Pim1 transgenic (Tx) mice bearing human PIM1 under the control of vav hematopoietic promoter (vav-hPIM1 Tx). Pim1−/−, Pim2−/−, Pim3−/− single knockout (KO) mice were also utilized. We quantified the number of hematopoietic stem/progenitor cells (HSPCs) in these mice using flow cytometry, colony forming units (CFUs) and cobblestone area forming cell colonies (CAFCs) assays. In vivo BrdU labeling was performed to determine the proliferation status of long-term HSCs in these mice. CXCR4 expression and the homing of HSCs to bone marrow and spleen were also analyzed. Additionally, we performed noncompetitive, competitive, and serial transplantation assays to examine the role of Pim1, Pim2 and Pim3 in hematological reconstitution in lethally irradiated recipient mice. Finally, a limiting dilution competitive bone marrow transplantation assay using purified long-term HSC cells (Lin− Sca-1+c-kit+ CD34−) was performed to calculate the frequency of active HSCs in vav-hPIM1 Tx and Pim1−/−mice. Results: Conclusion: Our current studies demonstrate a novel role of Pim1 serine/threonine kinase in the regulation of self-renewal, proliferation, and long-term repopulation of HSCs. The functions of Pim1 in hematopoiesis do not overlap with Pim2 or Pim3. Acknowledgment: We thank Richard Peppler at the Hollings Cancer Center Flow Cytometry Core for performing flow cytometry analysis. This work is supported by MUSC Hollings Cancer Center Startup Fund, Hollings Cancer Center ACS IRG, ASCO Conquer Cancer Foundation Career Development Award, NIH 1K08HL 103780–01A1, and NIH 3P30CA138313–01S3. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Silencing MASTL Inhibits Cell Proliferation and Migration of Gastric Cancer MGC-803 Cells Via Suprressing AKT, mTOR, p38 Signal Pathways

2020 ◽  
Author(s):  
caixia An ◽  
hailong li ◽  
Rong Niu ◽  
xiaoguang liu ◽  
Yonghua Hu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signal Pathways ◽  
Cyclin Dependent Kinase ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Mrna Microarray ◽  
And Migration

Abstract Background: Microtubule-associated serine/threonine kinase (MASTL) functions to regulate chromosome condensation and mitotic progression. Emerging reports showed that aberrant MASTL expression is commonly implicated in various human cancers and act as an oncogene. This study aimed to discover the potential significance of MASTL in gastric cancer, and to uncover relevant mechanisms. Methods: Lentivirus MASTL-shRNA was constructed and infected into MGC-803 cells to analysis its influences on cell proliferation by Green fluorescent protein (GFP)-based cellomics and colony formation assay, cell invasion and migration by transwell assay, apoptosis and cell cycle by flow cytometry detection, respectively. Nude mice and fluorescence imaging were used to characterize the regulation of tumor growth in vivo. Affymetrix mRNA microarray assay combined KEGG enrichment analysis were used to screen relevant molecules related to MASTL silencing. Finally，several aberrantly expressed genes were validated by quantitative reverse transcription PCR(RT-qPCR)and western blot detection. Results: Silencing MASTL significantly inhibited cell proliferation, migration and invasion, arrested cell cycle at G1 stage. Silencing MASTL reduced tumor growth in nude mice, and fluorescence imaging indicated that the total radiant efficiency of mice in the Lv-shMAST group was markedly reduced compared with in mice in the Lv-shCtrl group in vivo. Affymetrix mRNA microarray assay revealed that 124 genes upregulated, 167 genes downregulated. RT-qPCR and western blotting validation showed that cyclin dependent kinase 6(CDK6), bone morphogenetic protein 2(BMP2), snail family transcriptional repressor 2(SNAI2), phosphorylation-mechanistic target of rapamycin kinase (p-mTOR), phosphorylation-AKT serine/threonine kinase (p-AKT) and phosphorylation-p38 kinase (p-p38) are downregulated, and cyclin dependent kinase inhibitor 1A (CDKN1A) is upregulated. Conclusions: Silencing MASTL could significantly inhibit cell growth, migration ability, induce apoptosis, arrest cell cycle at G1 stage, and the mechanisms of which were mediated via inactivation of mTOR, AKT, p38 signal pathways.

scholarly journals Emerging Role of Aurora A in Radioresistance: A Comprehensive Review

EMJ Oncology ◽  
2021 ◽  
pp. 81-90
Author(s):  
Salini Das ◽  
Elizabeth Mahapatra ◽  
Souvick Biswas ◽  
Madhumita Roy ◽  
Sutapa Mukherjee
Keyword(s):  
Cell Cycle ◽  
Aurora Kinase ◽  
Cell Cycle Regulators ◽  
Aurora A ◽  
Regulatory Pathway ◽  
Serine Threonine Kinase ◽  
Altered Expression ◽  
Threonine Kinase ◽  
Functional Implications

Radiotherapy is one of the most conventional modes of treatment in several cancers. Failure of radiotherapy followed by acquisition of radioresistance is one of the emerging challenges faced by clinical experts. Unusual expression and functional implications of several molecules are observed to facilitate radioresistance. Aurora A, a member of the Aurora kinase (serine/threonine kinase) family, is one such molecule that shows significantly altered expression as well as non-canonical functional crosstalk with other associated factors (cell cycle regulators, signaling molecules, stemness markers, etc.) to favour the adaptations for the acquirement of radioresistance. These mechanisms include progression of cell cycle, stimulatory activation of factors by phosphorylation for enhancing the chance of cellular survivability, and prevention of apoptosis. This review article summarises how Aurora A is responsible for radioresistance in cancer and why this kinase should be considered a negative biomarker of radiosensitivity. This review discloses a wider opportunity in the field of research to find the mechanistic key regulatory pathway of Aurora A, which can be a potential target for enhancing the efficiency of treatment. Further investigations are required to explore the potential of Aurora A inhibitors as reliable radiosensitisers.

scholarly journals RIOK2 drives glioblastoma cell proliferation by modulating MYC through the RNA-binding protein IMP3

2020 ◽  
Author(s):  
Alexander S. Chen ◽  
Jhomar Marquez ◽  
Nathaniel H. Boyd ◽  
Se-Yeong Oh ◽  
Riley Gulbronson ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Protein Levels ◽  
Current Therapies ◽  
Human Gbm ◽  
Primary Malignant Brain Tumor

ABSTRACTGlioblastoma (GBM) is the most common primary malignant brain tumor and is resistant to current therapies. Here, using a combination of proteomic and genetic approaches in both Drosophila and human GBM models, we identify novel signaling effectors that act downstream of EGFR and PI3K signaling pathways, which drive GBM. Our results indicate that RIOK2, an atypical serine/threonine kinase, forms a complex with the RNA-binding protein, IMP3 (Imp in Drosophila), and that the dRIOK2/RIOK-Imp/IMP3 pathway is necessary for tumorigenesis. Furthermore, our results indicate that RIOK2 catalytic activity is important for neoplasia and recruits TORC2 to phosphorylate IMP3. Finally, the dRIOK2-Imp pathway regulates protein levels of dMyc, a known Imp target mRNA, and these key findings were recapitulated in human GBM models. Collectively, our data indicates that RIOK2 catalytic activity promotes the activation of TORC2 and recruitment of IMP3, which in turn, modulates MYC mRNA and protein levels to promote tumorigenesis.

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