| First Author | Saadatzadeh MR | Year | 2009 |
| Journal | Blood | Volume | 113 |
| Issue | 12 | Pages | 2655-60 |
| PubMed ID | 19168785 | Mgi Jnum | J:146877 |
| Mgi Id | MGI:3838705 | Doi | 10.1182/blood-2008-09-181420 |
| Citation | Saadatzadeh MR, et al. (2009) Distinct roles of stress-activated protein kinases in Fanconi anemia-type C-deficient hematopoiesis. Blood 113(12):2655-60 |
| abstractText | The underlying molecular mechanisms that promote bone marrow failure in Fanconi anemia are incompletely understood. Evidence suggests that enhanced apoptosis of hematopoietic precursors is a major contributing factor. Previously, enhanced apoptosis of Fanconi anemia type C-deficient (Fancc(-/-)) progenitors was shown to involve aberrant p38 MAPK activation. Given the importance of c-Jun N-terminal kinase (JNK) in the stress response, we tested whether enhanced apoptosis of Fancc(-/-) cells also involved altered JNK activation. In Fancc(-/-) murine embryonic fibroblasts, tumor necrosis factor alpha (TNF-alpha) induced elevated JNK activity. In addition, JNK inhibition protected Fancc(-/-) murine embryonic fibroblasts and c-kit(+) bone marrow cells from TNF-alpha-induced apoptosis. Importantly, hematopoietic progenitor assays demonstrated that JNK inhibition enhanced Fancc(-/-) colony formation in the presence of TNF-alpha. Competitive repopulation assays showed that Fancc(-/-) donor cells cultured with the JNK inhibitor had equivalent levels of donor chimerism compared with Fancc(-/-) donor cells cultured with vehicle control. In contrast, culturing Fancc(-/-) cells with a p38 MAPK inhibitor significantly increased repopulating ability, supporting an integral role of p38 MAPK in maintaining Fancc(-/-) hematopoietic stem cell function. Taken together, these data suggest that p38 MAPK, but not JNK, has a critical role in maintaining the engraftment of Fancc(-/-)-reconstituting cells under conditions of stress. |
