Basic FGF-induced activation of telomerase in rheumatoid synoviocytes

Tsumuki, H.; Hasunuma, Tomoko; Kobata, Tetsuji; Kato, Tomohiro; Uchida, Atsushi; Nishioka, Kusuki

doi:10.1007/s002960050115

Cited by 26 publications

(23 citation statements)

References 27 publications

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“…These findings are in agreement with studies in immortal cell lines and lymphocytes showing that telomerase activity is elevated in actively cycling cells but is downregulated in quiescent cells. 5,6 They also concur with reports showing that FGF-2 upregulates telomerase activity in neural precursor cells, 24 synoviocytes, 25 and lung fibroblasts. 26 Others have recently reported that cultured endothelial cells are telomerase competent and that activity is repressed on growth inhibition and replicative senescence.…”

Section: Discussionsupporting

confidence: 87%

Fibroblast Growth Factor-2, But Not Vascular Endothelial Growth Factor, Upregulates Telomerase Activity in Human Endothelial Cells

Kurz

Hong

Trivier

et al. 2003

ATVB

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Objective-Telomerase plays a major role in the control of replicative capacity, a critical property for successful angiogenesis and maintenance of endothelial integrity. In this study, we examined the relationship between telomerase activity and endothelial cell proliferation as well as the regulation of this enzyme by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-A (VEGF). Methods and Results-Telomerase was repressed in endothelial cells freshly derived from intact endothelium, whereas activity was present during logarithmic growth in culture. In cultured human umbilical vein endothelial cells (HUVECs), mRNA levels of hTERT-the catalytic subunit of telomerase-and enzyme activity decreased reversibly on induction of quiescence. Treatment of quiescent HUVECs with FGF-2 restored telomerase activity in a time-and dose-dependent manner, whereas VEGF had no such effect, although both factors induced comparable mitogenic responses. FGF-2, but not VEGF, upregulated the mRNA levels for hTERT and for the hTERT gene transactivation factor Sp1. Key Words: telomerase Ⅲ fibroblast growth factor-2 Ⅲ endothelial cell Ⅲ Sp1 Ⅲ senescence I nduction of angiogenesis is a novel therapeutic strategy presently being evaluated for the treatment of human ischemic vascular disease. The success of this strategy depends on an adequate proliferative response of vascular endothelial cells at the site of ischemia. 1 Cellular replicative potential is in part limited by the integrity of telomeres, the physical ends of chromosomal DNA. 2 Telomeric DNA shortens by Ϸ50 to 200 base pairs with each round of cell division as a consequence of the inability of conventional DNA polymerases to replicate the 3Ј termini of the template strands. A large body of evidence indicates that critical shortening of one or more telomeres activates a DNA damage checkpoint that blocks additional replication and leads to cell senescence. However, more recently, the integrity of the T-loop-a higher-order structure formed at the end of the telomere by telomeric DNA and specialized proteins-rather than telomere length, per se, has been implicated as a major determinant of senescence. 3,4 In many actively proliferating cells, maintenance of replicative capacity and chromosome stability requires the activity of telomerase, a specialized reverse-transcriptase that adds hexanucleotide repeats of the sequence TTAGGG to the 3Ј ends of nuclear DNA, thus counteracting telomeric erosion. 3 Studies in various immortalized cell lines 5 and normal human lymphocytes 6 have shown that like other enzymes involved in chromosomal DNA synthesis, 7 telomerase activity levels are differentially regulated during periods of proliferation and quiescence. Human telomerase consists of at least 3 subunits. Of these, the RNA component hTR, which provides the template for telomere synthesis, and the telomeraseassociated protein hTEP1 are constitutively expressed. 8,9 The third component, human telomerase reverse transcriptase (hTERT), which contains the catalytic activit...

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Section: Discussionsupporting

confidence: 87%

Fibroblast Growth Factor-2, But Not Vascular Endothelial Growth Factor, Upregulates Telomerase Activity in Human Endothelial Cells

Kurz

Hong

Trivier

et al. 2003

ATVB

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“…5, and Galligan CL: unpublished observations). Although RA fibroblast-like synoviocytes retain telomerase activity (6) and may exhibit decreased senescence, these cells are not immortalized in vitro. The outgrowth of fibroblast-like synoviocytes in the synovial tissue of affected RA joints is therefore an enigma.…”

Section: Conclusion Circulating Fibrocytes Migrate To Joints and Infmentioning

confidence: 99%

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Galligan¹,

Fish²

2012

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/ chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA.Methods. Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680.Results. The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation.Conclusion. Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis.

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“…In the absence of hTERT, telomere shortening occurs, which can allow end-to-end chromosomal fusion to form dicentric chromosomes that are prone to break during mitosis leading to aneuploidy or chromosomal rearrangements and translocations. hTERT expression is elevated in most cancer cells and leukemic ATL cells are no exception (Uchida et al, 1999;Tsumuki et al, 2001;Franzese et al, 2002). Interestingly, Tax has been shown to repress transcription from the hTERT promoter during mitogenic stimulation (Gabet et al, 2003), while activating hTERT expression in the absence of mitogenic stimulation (Sinha-Datta et al, 2004).…”

Section: Genome Instability and Htlv-i Infectionmentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

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Basic FGF-induced activation of telomerase in rheumatoid synoviocytes

Cited by 26 publications

References 27 publications

Fibroblast Growth Factor-2, But Not Vascular Endothelial Growth Factor, Upregulates Telomerase Activity in Human Endothelial Cells

Fibroblast Growth Factor-2, But Not Vascular Endothelial Growth Factor, Upregulates Telomerase Activity in Human Endothelial Cells

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

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