p53-Dependent transcriptional responses to interleukin-3 signaling

• Published in: PloS one Vol. 7; no. 2; p. e31428
• Main Authors: Jabbour, Anissa M, Gordon, Lavinia, Daunt, Carmel P, Green, Benjamin D, Kok, Chung H, D'Andrea, Richard, Ekert, Paul G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.02.2012; Public Library of Science (PLoS)
• Subjects: AKT protein; Animals; Apoptosis; Bcl-2 protein; Biology; Cell Survival; Cells (biology); Cellular stress response; Chemotherapy; Clonal deletion; Comparative analysis; Cooperation; Deoxyribonucleic acid; Deregulation; DNA; DNA damage; Extracellular signal-regulated kinase; Genetic aspects; Hematology; Hematopoietic stem cells; Interleukin 3; Interleukin-3 - metabolism; Interleukins; Intracellular signalling; Ionizing radiation; Kinases; Laboratories; MAP kinase; MAP Kinase Signaling System; Medical research; Medicine; Mice; Mutation; Myeloid cells; Myeloid Cells - cytology; Myeloid Cells - metabolism; p53 Protein; Proto-Oncogene Proteins c-akt; Signal Transduction; Survival; Transcription; Transcription (Genetics); Transcription, Genetic; Tumor proteins; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Australia; Victoria Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031428

p53 is critical in the normal response to a variety of cellular stresses including DNA damage and loss of p53 function is a common feature of many cancers. In hematological malignancies, p53 deletion is less common than in solid malignancies but is associated with poor prognosis and resistance to chemotherapy. Compared to their wild-type (WT) counterparts, hematopoietic progenitor cells lacking p53 have a greater propensity to survive cytokine loss, in part, due to the failure to transcribe Puma, a proapoptotic Bcl-2 family member. Using expression arrays, we have further characterized the differences that distinguish p53(-/-) cells from WT myeloid cells in the presence of Interleukin-3 (IL-3) to determine if such differences contribute to the increased clonogenicity and survival responses observed in p53(-/-) cells. We show that p53(-/-) cells have a deregulated intracellular signaling environment and display a more rapid and sustained response to IL-3. This was accompanied by an increase in active ERK1/2 and a dependence on an intact MAP kinase signaling pathway. Contrastingly, we find that p53(-/-) cells are independent on AKT for their survival. Thus, loss of p53 in myeloid cells results in an altered transcriptional and kinase signaling environment that favors enhanced cytokine signaling.