scholarly journals Self-Renewal Signalling in Presenescent Tetraploid IMR90 Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Anda Huna ◽  
Kristine Salmina ◽  
Elina Jascenko ◽  
Gunars Duburs ◽  
Inna Inashkina ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Normal Human Fibroblast ◽  
Malignant Growth ◽  
Self Renewal ◽  
Perinucleolar Compartment ◽  
Damage Response ◽  
Molecular Context ◽  
Normal Human ◽  
Fibroblast Model

Endopolyploidy and genomic instability are shared features of both stress-induced cellular senescence and malignant growth. Here, we examined these facets in the widely used normal human fibroblast model of senescence, IMR90. At the presenescence stage, a small (2–7%) proportion of cells overcome the 4n-G1 checkpoint, simultaneously inducing self-renewal (NANOG-positivity), the DNA damage response (DDR; γ-H2AX-positive foci), and senescence (p16inka4a- and p21CIP1-positivity) signalling, some cells reach octoploid DNA content and divide. All of these markers initially appear and partially colocalise in the perinucleolar compartment. Further, with development of senescence and accumulation of p16inka4a and p21CIP1, NANOG is downregulated in most cells. The cells increasingly arrest in the 4n-G1 fraction, completely halt divisions and ultimately degenerate. A positive link between DDR, self-renewal, and senescence signalling is initiated in the cells overcoming the tetraploidy barrier, indicating that cellular and molecular context of induced tetraploidy during this period of presenescence is favourable for carcinogenesis.

Sodium Butyrate Inhibits the Self-Renewal Capacity of Endometrial Tumor Side-Population Cells by Inducing a DNA Damage Response

2011 ◽  
Vol 10 (8) ◽  
pp. 1430-1439 ◽  
Author(s):  
Kiyoko Kato ◽  
Aya Kuhara ◽  
Tomoko Yoneda ◽  
Takafumi Inoue ◽  
Tomoka Takao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Sodium Butyrate ◽  
Side Population ◽  
The Self ◽  
Side Population Cells ◽  
Self Renewal ◽  
Endometrial Tumor ◽  
Damage Response

Zoledronic acid induces S-phase arrest via a DNA damage response in normal human oral keratinocytes

2012 ◽  
Vol 57 (7) ◽  
pp. 906-917 ◽  
Author(s):  
Hisashi Ohnuki ◽  
Kenji Izumi ◽  
Michiko Terada ◽  
Taro Saito ◽  
Hiroko Kato ◽  
...  
Keyword(s):  
Dna Damage ◽  
Zoledronic Acid ◽  
Dna Damage Response ◽  
S Phase ◽  
Oral Keratinocytes ◽  
Phase Arrest ◽  
Damage Response ◽  
S Phase Arrest ◽  
Normal Human

scholarly journals A Distinctive DNA Damage Response in Human Hematopoietic Stem Cells Reveals an Apoptosis-Independent Role for p53 in Self-Renewal

2010 ◽  
Vol 7 (2) ◽  
pp. 186-197 ◽  
Author(s):  
Michael Milyavsky ◽  
Olga I. Gan ◽  
Magan Trottier ◽  
Martin Komosa ◽  
Ofer Tabach ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Dna Damage Response ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Damage Response

A MODEL to STUDY the Function of NPM-MLF1 IN MYELODYSPLASIA.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1571-1571
Author(s):  
Wen-hsin Lee
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Conflicts Of Interest ◽  
Mouse Bone Marrow ◽  
Self Renewal ◽  
Damage Response ◽  
Elevated Expression

Abstract Abstract 1571 Myelodysplastic syndromes (MDS) are bone marrow disorders characterized by ineffective haematopoiesis and peripheral cytopenia(s) with frequent evolution to acute myeloid leukemia (AML). Apoptosis is significantly deregulated in early MDS whereas advanced MDS is characterized by deregulation of DNA damage response. As MDS proceeds to AML, the ratio of apoptosis to proliferation decreases, resulting in clonal outgrowth of abnormal cells. The t(3;5)(q25;q34) translocation, creating the NPM-MLF1 fusion, has been found as a sole cytogenetic abnormality in MDS. It is recurrent, with poor prognosis but the precise mechanism through which NPM-MLF1 induces malignant transformation remains unknown. We aimed to model this disease in vitro and in vivo by expressing NPM-MFL1 in mouse bone marrow hematopoietic progenitor cells (HPCs) and analyzing any changes in HPC self-renewal and response to DNA damage. NPM-MLF1 did not impair haematopoiesis in vitro and in vivo. FLT3/ITD was frequently associated with NPM mutant in AML patients; however, NPM-MLF1 did not collaborate with FLT3/ITD in our system. To recapitulate NPM hemizygosity in t(3;5)-MDS patients, we have expressed NPM-MLF1 in HPCs derived from Npm+/− mice. A transient increase in the self-renewal of the NPM-MLF1-expressing Npm+/− HPCs was seen. These cells did not exhibit enhanced proliferation as confirmed by growth curve and analysis of DNA synthesis. Interestingly, unlike control cells, NPM-MLF1-expressing Npm+/− HPCs showed prolonged self-renewal ability in vitro, and an elevated expression of c-Myc, Hoxa9, Hoxa10 and Meis1 genes. In addition to altering HPC self-renewal, NPM-MLF1 was also found to modulate their DNA damage response. This study suggests that the ability of NPM-MLF1 to maintain HPC self-renewal and impaired DNA damage responses may favour the accumulation and outgrowth of the aberrant HPCs, contributing to the abnormal haematopoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Zinc Deficiency Alters DNA Damage Response Genes in Normal Human Prostate Epithelial Cells

2008 ◽  
Vol 138 (4) ◽  
pp. 667-673 ◽  
Author(s):  
Michelle Yan ◽  
Yang Song ◽  
Carmen P. Wong ◽  
Karin Hardin ◽  
Emily Ho
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Dna Damage Response ◽  
Zinc Deficiency ◽  
Human Prostate ◽  
Prostate Epithelial Cells ◽  
Damage Response ◽  
Normal Human
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