scholarly journals CDK6 kinase activity is required for thymocyte development

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6120-6131 ◽  
Author(s):  
Miaofen G. Hu ◽  
Amit Deshpande ◽  
Nicolette Schlichting ◽  
Elisabeth A. Hinds ◽  
Changchuin Mao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Kinase Activity ◽  
Thymocyte Development ◽  
Hematopoietic Stem ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
Lymphoid Malignancies ◽  
Proliferation And Differentiation

Abstract Cyclin-dependent kinase-6 (CDK6) is required for early thymocyte development and tumorigenesis. To mechanistically dissect the role of CDK6 in thymocyte development, we generated and analyzed mutant knock-in mice and found that mice expressing a kinase-dead Cdk6 allele (Cdk6K43M) had a pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells (Lin−Sca-1+c-Kit+ [LSK]). In contrast, mice expressing the INK4-insensitive, hyperactive Cdk6R31C allele displayed excess proliferation in LSK and thymocytes. However, this is countered at least in part by increased apoptosis, which may limit progenitor and thymocyte expansion in the absence of other genetic events. Our mechanistic studies demonstrate that CDK6 kinase activity contributes to Notch signaling because inactive CDK6 kinase disrupts Notch-dependent survival, proliferation, and differentiation of LSK, with concomitant alteration of Notch target gene expression, such as massive up-regulation of CD25. Further, knockout of CD25 in Cdk6K43M mice rescued most defects observed in young mice. These results illustrate an important role for CDK6 kinase activity in thymocyte development that operates partially through modulating Notch target gene expression. This role of CDK6 as a downstream mediator of Notch identifies CDK6 kinase activity as a potential therapeutic target in human lymphoid malignancies.

Relationship between Radiosensitivity and Nrf2 Target Gene Expression in Human Hematopoietic Stem Cells

2010 ◽  
Vol 174 (2) ◽  
pp. 177-184 ◽  
Author(s):  
Kengo Kato ◽  
Kenji Takahashi ◽  
Satoru Monzen ◽  
Hiroyuki Yamamoto ◽  
Atsushi Maruyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Target Gene ◽  
Hematopoietic Stem ◽  
Target Gene Expression ◽  
Nrf2 Target Gene

scholarly journals E2f1, E2f2, and E2f3 Control E2F Target Expression and Cellular Proliferation via a p53-Dependent Negative Feedback Loop

2007 ◽  
Vol 27 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Cynthia Timmers ◽  
Nidhi Sharma ◽  
Rene Opavsky ◽  
Baidehi Maiti ◽  
Lizhao Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Control Of Gene Expression ◽  
Target Gene Expression ◽  
Rb Phosphorylation ◽  
P53 Target Genes

ABSTRACT E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21 CIP1 . Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2f3-deficient cells, either by spontaneous mutation or by conditional gene ablation, prevented the induction of p21 CIP1 and many other p53 target genes. As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals. These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation.

scholarly journals Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

2006 ◽  
Vol 26 (1) ◽  
pp. 209-220 ◽  
Author(s):  
Alexis Dumortier ◽  
Robin Jeannet ◽  
Peggy Kirstetter ◽  
Eva Kleinmann ◽  
MacLean Sellars ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Target Gene ◽  
Critical Role ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
T Cell Leukemogenesis ◽  
Notch Activation

ABSTRACT The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (IkL/L) in the Ikaros gene all develop thymic lymphomas. IkL/L tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young IkL/L mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.

scholarly journals Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

2018 ◽  
Author(s):  
Ian Huck ◽  
Sumedha Gunewardena ◽  
Regina Espanol-Suner ◽  
Holger Willenbring ◽  
Udayan Apte
Keyword(s):  
Gene Expression ◽  
Liver Regeneration ◽  
Target Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatic Differentiation ◽  
Target Gene Expression ◽  
Protein Levels ◽  
Hepatocyte Nuclear Factor 4

AbstractHepatocyte Nuclear Factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4α in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during liver regeneration. Western blot analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels accompanied with decreased target gene expression within 1 hour after 2/3 partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to the pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO) in mice resulted in 100% mortality post-PH despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by c-myc and cyclin D1 over expression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes did not prevent initiation of regeneration after PH. Finally, AAV8-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression and improved survival of HNF4α-KO mice post-PH. In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of liver regeneration. These results reveal the role of HNF4α in liver regeneration and have implications for therapy of liver failure.

scholarly journals Down-regulation of notch target gene expression by suppressor of deltex

2003 ◽  
Vol 255 (2) ◽  
pp. 363-372 ◽  
Author(s):  
Sabine L Mazaleyrat ◽  
Maggy Fostier ◽  
Marian B Wilkin ◽  
Hanna Aslam ◽  
Dana A.P Evans ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Down Regulation ◽  
Notch Target Gene ◽  
Target Gene Expression

Prostaglandin E2promotes neural proliferation and differentiation and regulates Wnt target gene expression

2016 ◽  
Vol 94 (8) ◽  
pp. 759-775 ◽  
Author(s):  
Christine T. Wong ◽  
Netta Ussyshkin ◽  
Eizaaz Ahmad ◽  
Ravneet Rai-Bhogal ◽  
Hongyan Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Target Gene Expression ◽  
Proliferation And Differentiation

Abstract 13: Development of Functionalized Nanoparticle Platform for Reducing Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Shobha Ghosh ◽  
Jing Wang ◽  
Jinghua Bie ◽  
Quan Yuan ◽  
Olga Zolotarskaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Studies ◽  
Target Gene ◽  
Foam Cells ◽  
Expression Vectors ◽  
Transgenic Expression ◽  
Target Gene Expression ◽  
Macrophage Foam Cells ◽  
Plaque Regression

No therapy is currently available to enhance the removal of cholesteryl esters (CE) from existing atherosclerotic plaques to facilitate plaque regression. Such a strategy is crucial to reduce the burden of existing disease in addition to preventing the progression targeted by the current therapeutics. Earlier studies from our laboratory have established the anti-atherogenic role of CE hydrolase (CEH)-mediated CE mobilization from macrophage foam cells and final elimination of cholesterol by the liver. While transgenic expression of CEH was used in pre-clinical animal studies, increase in human CEH by activation of Liver-X-receptor (LXR) was also established. Increased lipogenesis induced by LXR ligands precludes their use. The current studies focused on the development of mannose-functionalized dendrimer nanoparticles (DNPs) for the delivery of LXR ligand (TO901317) or CEH expression vector to plaque associated macrophage foam cells. As shown in the Figure, mannose functionalization restricts the uptake of DNPs to macrophages and minimal uptake was seen with primary hepatocytes ( A ). Western diet fed LDLR-/- mice were injected (iv) with DNPs and tissues harvested 48 later to monitor gene expression by QPCR. DNP-mediated delivery of LXR ligand (DNP-LXR) increased the target gene expression (ABCA1, ABCG1) in plaque associated macrophage foam cells in the aortic arch with no effects on target gene expression in the liver ( B ) demonstrating the specific delivery of LXR ligand. Comparable increase in CEH activity was seen following exposure of macrophages to free LXR ligand and DNP-delivered LXR ligand ( C ) and DNP-mediated delivery of CEH expression vectors driven either by CMV or SR-A promoter induced dramatic increase in CEH expression ( D ). These data establish functionalized DNP as a suitable platform for specific and functional delivery of drugs or DNA to plaque associated macrophages to enhance processes involved in cholesterol removal and plaque regression.

scholarly journals Osteogenic Oxysterol, 20(S)-Hydroxycholesterol, Induces Notch Target Gene Expression in Bone Marrow Stromal Cells

2009 ◽  
pp. 091019190442039-37 ◽  
Author(s):  
Woo-Kyun Kim ◽  
Vicente Meliton ◽  
Sotirios Tetradis ◽  
Gerry Weinmaster ◽  
Theodore J Hahn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Target Gene ◽  
Marrow Stromal Cells ◽  
Notch Target Gene ◽  
Target Gene Expression
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