scholarly journals c-Jun transactivates Puma gene expression to promote osteoarthritis

2014 ◽  
Vol 9 (5) ◽  
pp. 1606-1612 ◽  
Author(s):  
HUADING LU ◽  
GANG HOU ◽  
YONGKAI ZHANG ◽  
YUHU DAI ◽  
HUIQING ZHAO
Keyword(s):  
2016 ◽  
Vol 1 (1) ◽  
pp. 7
Author(s):  
Wael AbdelMageed ◽  
Rasha Fathy ◽  
Mohamed Othman

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 387-387
Author(s):  
Fu-Sheng Chou ◽  
Mark Wunderlich ◽  
James C. Mulloy

Abstract Abstract 387 A subset of acute myeloid leukemia (AML) is caused by chromosomal translocation (8;21), resulting in the expression of the AML1-ETO (AE) fusion protein. We have recently shown that AE represses DNA damage repair genes, resulting in increased DNA damage and upregulation of p53. These findings suggest that AE contributes to leukemogenesis by promoting additional mutations. However, it remains undefined how AE cells survive in the context of increased p53. In the current study, we showed that Bcl-xL is upregulated upon AE expression. Bcl-xL knockdown resulted in growth disadvantage and increased apoptosis in AE cells, but not in normal CD34+ cells. On the other hand, Bcl-xL overexpression in AE cells leads to an expansion of colony-forming cells and an increase in the frequency of long-term culture-initiating cells (LTC-IC). Interestingly, similar results were obtained when a Bcl-xL mutant (Bcl-xLG138A) that is defective in BH3 binding is overexpressed in AE cells, suggesting that the additional cytoprotection is not contributed by pro-apoptotic protein binding. Instead, published evidence on the p53 sequestering function of Bcl-xL prompted us to speculate that AE expression may lead to the establishment of a new balance between pro-apoptotic signals conveyed by activated p53 and the pro-survival characteristic of Bcl-xL. Indeed, using confocal microscopy, we observed colocalization of Bcl-xL and p53 in CD34+ AE cells. In addition, we also observed an increase in p53 target gene expression in AE cells following Bcl-xL knockdown, implicating interplay between Bcl-xL levels and p53 activity. Strikingly, examination of the two critical apoptosis-inducing p53 downstream targets, Bim and Puma, revealed that, whereas Bim is upregluated in AE cells, Puma is downregulated upon AE expression. AE ablation in an established cell line induces Puma expression. A chromatin immunoprecipitation assay revealed that AE binds to the first intron of the Puma gene. These data suggest that AE directly represses Puma gene expression, thereby preventing Puma-induced dissociation of p53 from Bcl-xL. Taken together, our in vitro findings demonstrated that the interplay among p53, Bcl-xL and Puma in response to DNA damage in normal cellular physiology is disrupted in the presence of AE to ensure cell survival. To recapitulate the critical role of Bcl-xL in AE expressing cells in an in vivo xenotransplantation assay, we transduced scrambled and Bcl-xL shRNA into AE/N-RASG12D cells, followed by transplantation into the bone marrow cavity of immunodeficient mice. We found that Bcl-xL knockdown is associated with a significant reduction in the long-term engraftment capability of AE/N-RASG12D cells. In conclusion, our data indicate that AE expressing human hematopoietic cells depend on Bcl-xL for their survival and growth. Disclosures: No relevant conflicts of interest to declare.


2008 ◽  
Vol 27 (1) ◽  
pp. 44 ◽  
Author(s):  
Xinying Wang ◽  
Jing Wang ◽  
Shiyong Lin ◽  
Yan Geng ◽  
Jide Wang ◽  
...  

Author(s):  
W. K. Jones ◽  
J. Robbins

Two myosin heavy chains (MyHC) are expressed in the mammalian heart and are differentially regulated during development. In the mouse, the α-MyHC is expressed constitutively in the atrium. At birth, the β-MyHC is downregulated and replaced by the α-MyHC, which is the sole cardiac MyHC isoform in the adult heart. We have employed transgenic and gene-targeting methodologies to study the regulation of cardiac MyHC gene expression and the functional and developmental consequences of altered α-MyHC expression in the mouse.We previously characterized an α-MyHC promoter capable of driving tissue-specific and developmentally correct expression of a CAT (chloramphenicol acetyltransferase) marker in the mouse. Tissue surveys detected a small amount of CAT activity in the lung (Fig. 1a). The results of in situ hybridization analyses indicated that the pattern of CAT transcript in the adult heart (Fig. 1b, top panel) is the same as that of α-MyHC (Fig. 1b, lower panel). The α-MyHC gene is expressed in a layer of cardiac muscle (pulmonary myocardium) associated with the pulmonary veins (Fig. 1c). These studies extend our understanding of α-MyHC expression and delimit a third cardiac compartment.


2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.


2013 ◽  
Vol 54 ◽  
pp. 79-90 ◽  
Author(s):  
Saba Valadkhan ◽  
Lalith S. Gunawardane

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.


2006 ◽  
Vol 73 ◽  
pp. 85-96 ◽  
Author(s):  
Richard J. Reece ◽  
Laila Beynon ◽  
Stacey Holden ◽  
Amanda D. Hughes ◽  
Karine Rébora ◽  
...  

The recognition of changes in environmental conditions, and the ability to adapt to these changes, is essential for the viability of cells. There are numerous well characterized systems by which the presence or absence of an individual metabolite may be recognized by a cell. However, the recognition of a metabolite is just one step in a process that often results in changes in the expression of whole sets of genes required to respond to that metabolite. In higher eukaryotes, the signalling pathway between metabolite recognition and transcriptional control can be complex. Recent evidence from the relatively simple eukaryote yeast suggests that complex signalling pathways may be circumvented through the direct interaction between individual metabolites and regulators of RNA polymerase II-mediated transcription. Biochemical and structural analyses are beginning to unravel these elegant genetic control elements.


2002 ◽  
Vol 69 ◽  
pp. 135-142 ◽  
Author(s):  
Elena M. Comelli ◽  
Margarida Amado ◽  
Steven R. Head ◽  
James C. Paulson

The development of microarray technology offers the unprecedented possibility of studying the expression of thousands of genes in one experiment. Its exploitation in the glycobiology field will eventually allow the parallel investigation of the expression of many glycosyltransferases, which will ultimately lead to an understanding of the regulation of glycoconjugate synthesis. While numerous gene arrays are available on the market, e.g. the Affymetrix GeneChip® arrays, glycosyltransferases are not adequately represented, which makes comprehensive surveys of their gene expression difficult. This chapter describes the main issues related to the establishment of a custom glycogenes array.


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