KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 725-732 ◽  
Author(s):  
Grzegorz Sarek ◽  
Annika Järviluoma ◽  
Päivi M. Ojala
Keyword(s):  
Cell Cycle ◽  
Kaposi Sarcoma ◽  
Lytic Cycle ◽  
Down Regulation ◽  
P27kip1 Protein ◽  
Protein Levels ◽  
Inhibitory Function ◽  
Viral Cyclin ◽  
Regulation Of Cell Cycle ◽  
Primary Effusion Lymphomas

AbstractKaposi sarcoma herpesvirus (KSHV) infection is consistently associated with primary effusion lymphomas (PELs) that are non-Hodgkin lymphomas of B-cell origin. All PEL cells are latently infected with KSHV and express latent viral proteins such as the viral cyclin (v-cyclin), which has previously been implicated in down-regulation of cell-cycle inhibitor p27KIP1 levels via phosphorylation on Thr187. PEL cells retain high levels of p27KIP1 but yet proliferate actively, which has left the biologic significance of this p27KIP1 destabilization somewhat elusive. We have recently demonstrated that v-cyclin and p27KIP1 stably associate in PEL cells. Here we demonstrate that v-cyclin together with its kinase partner CDK6 phosphorylates the associated p27KIP1 in PEL cells, which represent a biologically relevant model system for KSHV pathobiology. During latent viral replication p27KIP1 was phosphorylated by v-cyclin-CDK6 predominantly on Ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of KSHV lytic cycle, v-cyclin-CDK6 phosphorylated p27KIP1 on Thr187, which resulted in down-regulation of p27KIP1 protein levels. These findings indicate that v-cyclin modulates the cell-cycle inhibitory function of p27KIP1 by phosphorylation in PELs, and also suggest a novel role for v-cyclin in the lytic reactivation of KSHV. (Blood. 2006;107:725-732)

KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3349-3354 ◽  
Author(s):  
Annika Järviluoma ◽  
Sonja Koopal ◽  
Susanna Räsänen ◽  
Tomi P. Mäkelä ◽  
Päivi M. Ojala
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Kaposi Sarcoma ◽  
Cyclin Dependent Kinase ◽  
Cell Cycle Inhibitor ◽  
Non Hodgkin Lymphoma ◽  
Viral Cyclin ◽  
Primary Effusion Lymphomas ◽  
Proliferative Signal

Abstract Primary effusion lymphomas (PELs) represent a unique non-Hodgkin lymphoma that is consistently infected by Kaposi sarcoma herpesvirus (KSHV). PEL cells express high levels of the cell cycle inhibitor p27KIP1 and yet proliferate actively. KSHV genome encodes a viral cyclin homolog, v-cyclin, which has previously been implicated in down-regulation of p27KIP1 levels. To address how PEL cells can tolerate high p27KIP1 levels, we investigated functional interactions between v-cyclin and p27KIP1 using PEL-derived cell lines as a model system. Here we demonstrate that v-cyclin and p27KIP1 stably associate in PEL cells in vivo suggesting an attractive model by which p27KIP1 is inactivated in the actively proliferating PEL cells. Moreover, we show that v-cyclin and cyclin-dependent kinase 6 (CDK6) form an active kinase without p27KIP1 and that CDK6 is the in vivo catalytic subunit of v-cyclin in PEL cells. These findings suggest that KSHV may promote oncogenesis in PEL by expressing v-cyclin, which both overrides negative cell cycle controls present in the PEL precursor cells and induces a strong proliferative signal via CDK6 kinase activity. (Blood. 2004;104:3349-3354)

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals Elicitor-induced down-regulation of cell cycle-related genes in tobacco cells

2006 ◽  
Vol 29 (2) ◽  
pp. 183-191 ◽  
Author(s):  
KAORU SUZUKI ◽  
TAKUMI NISHIUCHI ◽  
YUKO NAKAYAMA ◽  
MASAKI ITO ◽  
HIDEAKI SHINSHI
Keyword(s):  
Cell Cycle ◽  
Down Regulation ◽  
Tobacco Cells ◽  
Regulation Of Cell Cycle

scholarly journals Regulation of Skp2 Expression and Activity and Its Role in Cancer Progression

2010 ◽  
Vol 10 ◽  
pp. 1001-1015 ◽  
Author(s):  
Chia-Hsin Chan ◽  
Szu-Wei Lee ◽  
Jing Wang ◽  
Hui-Kuan Lin
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Protein Levels ◽  
Human Cancers ◽  
Attractive Therapeutic Target ◽  
Skp2 Protein ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

The regulation of cell cycle entry is critical for cell proliferation and tumorigenesis. One of the key players regulating cell cycle progression is the F-box protein Skp2. Skp2 forms a SCF complex with Skp1, Cul-1, and Rbx1 to constitute E3 ligase through its F-box domain. Skp2 protein levels are regulated during the cell cycle, and recent studies reveal that Skp2 stability, subcellular localization, and activity are regulated by its phosphorylation. Overexpression of Skp2 is associated with a variety of human cancers, indicating that Skp2 may contribute to the development of human cancers. The notion is supported by various genetic mouse models that demonstrate an oncogenic activity of Skp2 and its requirement in cancer progression, suggesting that Skp2 may be a novel and attractive therapeutic target for cancers.

scholarly journals In Vitro CSC-derived Cardiomyocytes Exhibit the Typical microRNA-mRNA Blueprint of Endogenous Cardiomyocytes

2021 ◽  
Author(s):  
Mariangela Scalise ◽  
Fabiola Marino ◽  
Luca Salerno ◽  
Mancuso Teresa ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Differentiation ◽  
Down Regulation ◽  
Stem Cell Expansion ◽  
Cell Cycle Genes ◽  
Neonatal Cardiomyocytes ◽  
Gene Regulatory ◽  
Regulation Of Cell Cycle

Abstract miRNAs modulate cardiomyocyte specification in embryonic hearts and in pluripotent stem cells by targeting mRNAs of cell cycle regulators and acting in gene regulatory loops that complete commitment to the cardiac muscle lineage. It is still unknown if/to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). RNASeq comparison of “CSCs vs. iCMs” mRNome and microRNome showed a balanced up-regulation of sarcomere and mitochondrial related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs did not reach the levels of mouse terminally differentiated adult cardiomyocytes (aCMs), while they get to intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs while those miRs positively regulating stem cell expansion and self-renewal were down-regulated. The specific networks of miRNA/mRNAs operative in iCMs closely resembled miRNA/mRNA networks of aCMs. Two of these miRs, miR-1 and miR-499, enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of aCMs.

Involvement of DNA-dependent protein kinase in down-regulation of cell cycle progression

2003 ◽  
Vol 35 (4) ◽  
pp. 432-440 ◽  
Author(s):  
Fumiaki Watanabe ◽  
Ken-ichi Shinohara ◽  
Hirobumi Teraoka ◽  
Kenshi Komatsu ◽  
Kouichi Tatsumi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Progression ◽  
Down Regulation ◽  
Dependent Protein Kinase ◽  
Cycle Progression ◽  
Dependent Protein ◽  
Regulation Of Cell Cycle

scholarly journals In vitro CSC-derived cardiomyocytes exhibit the typical microRNA-mRNA blueprint of endogenous cardiomyocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mariangela Scalise ◽  
Fabiola Marino ◽  
Luca Salerno ◽  
Teresa Mancuso ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Differentiation ◽  
Down Regulation ◽  
Cell Cycle Genes ◽  
Neonatal Cardiomyocytes ◽  
Gene Regulatory ◽  
Regulation Of Cell Cycle

AbstractmiRNAs modulate cardiomyocyte specification by targeting mRNAs of cell cycle regulators and acting in cardiac muscle lineage gene regulatory loops. It is unknown if or to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). Comparison of “CSCs vs. iCMs” mRNome and microRNome showed a balanced up-regulation of CM-related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs reached intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs. The specific networks of miRNA/mRNAs operative in iCMs closely resembled those of adult CMs (aCMs). miR-1 and miR-499 enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of CMs.

Elevation of Kinase Interacting with Stathmin (KIS) and Promotion of Cellcycle Progression by KIS in Leukemia Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1365-1365
Author(s):  
Satoki Nakamura ◽  
Takaaki Ono ◽  
Yuya Sugimoto ◽  
Miki Kobayashi ◽  
Naohi Sahara ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Biological Significance ◽  
Small Population ◽  
Molecular Therapy ◽  
Leukemia Cells ◽  
G1 Arrest ◽  
Down Regulation ◽  
Cycle Progression ◽  
Regulation Of Cell Cycle

Abstract Purpose: The protein p27 is an important regulator of cell cycle. An increase in p27 causes proliferation of cells, while a decrease in p27 induces quiescence of cells. p27 is regulated by transcriptional, translational and proteolytic mechanisms. Among them, an importnant mechanism in the regulation of p27 is proteolysis. Kinase interacting with stathmin, KIS, is a serine / threonine kinase, and regulates cell cycle progression through the phosphorylation of p27 on serine 10. The S10 phosphorylation on p27 plays an important role in p27 degradation. KIS that phosphorylates p27 on S10 and its role in the regulation of cell cycle progression have not been defined in leukemia cells. In this study, we investigated the role of KIS in leukemia cells. Materials and Methods: We examined the biological significance of KIS expression in K562, NB4, U937, CEM, MOLT4, and SUP-B15 leukemia cells and relationship with the G1 regulaters, such as p27. Moreover, we generated the lentivirus vector inserted with the dsDNA of KIS small interfering RNA (siRNA), and effects of down-regulation of KIS by siRNA transfection were investigated in leukemia cells. Results: RT-PCR and western blot analysis showed high KIS expression in all leukemia cells. The p27 phosphorylation on S10 was significantly lower in the leukemia cells transduced with KIS siRNA and depletion of KIS enhanced growth arrest. The down-regulation of KIS induced G1 arrest in cell cycle, but not apoptosis. In cell cycle analysis, control leukemia cells showed 42.3 ± 1.8 %, but leukemia cells transfected with KIS siRNA showed 67,1 ± 2.1 % in G1 fraction. Moreover, these cells significantly showed small population in S ansd G2 fractions compared compared with controls. Conclusion: These findings suggest KIS expression promotes cell cycle progression in leukemia cells. Depletion of KIS using siRNA in leukemia cells induced cell cycle arrest in G1 phase compared with control cells. In this study, we showed that KIS might be the target for the molecular therapy.

Sign in / Sign up

Export Citation Format

Share Document