Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation

Jabbour, AM; Daunt, CP; Green, BD; Vogel, S; Gordon, L; Lee, RS; Silke, N; Pearson, RB; Vandenberg, CJ; Kelly, PN; Nutt, SL; Strasser, A; Borner, C; Ekert, PG

Author(s): Jabbour, AM; Daunt, CP; Green, BD; Vogel, S; Gordon, L; Lee, RS; Silke, N; Pearson, RB; Vandenberg, CJ; Kelly, PN; Nutt, SL; Strasser, A; Borner, C; Ekert, PG;
Details: Publication Year 2010-01-14,Volume 115,Issue #2,Page 344-352
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: Loss of p53-dependent apoptosis contributes to the development of hematologic malignancies and failure to respond to treatment. Proapoptotic Bcl-2 family member Puma is essential for apoptosis in HoxB8-immortalized interleukin-3 (IL-3)dependent myeloid cell lines (FDM cells) provoked by IL-3 deprivation. p53 and FoxO3a can transcriptionally regulate Puma. To investigate which transcriptional regulator is responsible for IL-3 deprivation-induced Puma expression and apoptosis, we generated wild-type (WT), p53(-/-), and FoxO3a(-/-) FDM cells and found that p53(-/-) but not FoxO3a(-/-) cells were protected against IL-3 withdrawal. Loss of p21(cip/waf), which is critical for p53-mediated cell-cycle arrest, afforded no protection against IL-3 deprivation. A survival advantage was also observed in untransformed p53(-/-) hemato poietic progenitor cells cultured in the presence or absence of cytokines. In response to IL-3 deprivation, increased Puma protein levels in p53(-/-) cells were substantially delayed compared with WT cells. Increased p53 transcriptional activity was detected after cytokine deprivation. This was substantially less than that induced by DNA damage and associated not with increased p53 protein levels but with loss of the p53 regulator, MDM2. Thus, we conclude that p53 protein is activated after IL-3 deprivation by loss of MDM2. Activated p53 transcriptionally upregulates Puma, which initiates apoptosis. (Blood. 2010; 115: 344-352)
Publisher: AMER SOC HEMATOLOGY
Keywords: BH3-ONLY PROTEINS PUMA; INDUCED APOPTOSIS; DNA-DAMAGE; TUMOR SUPPRESSION; BCL-2 FAMILY; CYCLE ARREST; DEATH; BIM; LEUKEMIA; PATHWAY
Publisher's Version: https://doi.org/10.1182/blood-2009-07-230730
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-01-14 12:00:00