The ATR-p53 pathway is suppressed in noncycling normal and malignant lymphocytes
| Autor: | Andrew R. Pettitt, Philip Michael Reaper, Gillian G Jones, Paul D. Sherrington |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
Ultraviolet Rays DNA repair DNA damage Lymphocyte Mitosis Biology medicine.disease_cause Peripheral blood mononuclear cell Reference Values Tumor Cells Cultured Genetics medicine Humans Lymphocytes Molecular Biology Cells Cultured DNA Primers Base Sequence Reverse Transcriptase Polymerase Chain Reaction Cell Cycle DNA Neoplasm Cell cycle Leukemia Lymphocytic Chronic B-Cell medicine.anatomical_structure Apoptosis Cell culture Cancer research Tumor Suppressor Protein p53 Carcinogenesis DNA Damage |
| Zdroj: | Oncogene. 23:1911-1921 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1207318 |
| Popis: | Chronic lymphocytic leukaemia (CLL) results from the accumulation of apoptosis-resistant clonal B cells that are arrested in G0/G1, and is heterogeneous with respect to clinical outcome. An aggressive form of the disease is identified by an impaired p53 response to ionizing radiation (IR). This is associated with inactivating mutations of either p53 or ATM, a regulator of p53 activated by IR-induced DNA damage. Since other forms of DNA damage activate p53 via ATR, a kinase closely related to ATM, abnormalities of the ATR-p53 pathway also have the potential to result in p53 dysfunction. We therefore tested cases of CLL for abnormal p53 responses to ultraviolet irradiation (UVC), a known activator of ATR, to screen for additional forms of p53 dysfunction. CLL cells and normal peripheral blood mononuclear cell (PBMC) preparations (predominantly noncycling lymphocytes) were treated with UVC and assessed for p53 responses. In all of the CLL cases and PBMC preparations tested, we were unable to detect p53 accumulation, phosphorylation or transcriptional consequences in response to UVC-induced DNA damage. The most likely explanation for the absence of UVC-induced p53 activation in CLL and normal lymphocytes was that, in contrast to other cell types, the UVC-induced ATR pathway was inactive. This notion was confirmed by showing that ATR protein was absent or undetectable in all of the cases of CLL and normal PBMCs screened. This was an unexpected finding because ATR was thought to be essential for the viability of somatic cells and for normal human and murine embryonic development. An obvious difference between the cell lines used as positive controls for ATR antibodies and the CLL cells/PBMCs was that the former were actively cycling while the latter were quiescent. We therefore hypothesized that the ATR-p53 pathway is selectively downregulated in noncycling lymphocytes. To test this, we induced cycling in the T-cell fraction of PBMC preparations and demonstrated that ATR protein expression was restored. Furthermore, p53 was upregulated and phosphorylated in response to UVC in these cells. Our data support the conclusion that the ATR-p53 pathway is suppressed in noncycling lymphocytes via ATR downregulation. We tentatively suggest that this repressed DNA damage response may have evolved to protect quiescent lymphocytes from the potential for p53-dependent apoptosis in the face of some forms of endurable genotoxic stress. If this is the case, DNA repair and genome stability might be compromised in quiescent lymphocytes with potentially negative consequences. |
| Databáze: | OpenAIRE |
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