Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice
Protein & Cell
;
(12): 80-89, 2014.
Article
in English
| WPRIM
| ID: wpr-757528
ABSTRACT
Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pathology
/
DNA Damage
/
Hematopoietic Stem Cells
/
Nuclear Proteins
/
B-Lymphocytes
/
T-Lymphocytes
/
Leukemia
/
Tumor Suppressor Protein p53
/
Mice, Knockout
/
Hematopoietic Stem Cell Transplantation
Limits:
Animals
Language:
English
Journal:
Protein & Cell
Year:
2014
Type:
Article
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