Abstract
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.
| Language | English |
|---|---|
| Article number | e31428 |
| Journal | PloS one |
| Volume | 7 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 14 Feb 2012 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
Cite this
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p53-dependent transcriptional responses to interleukin-3 signaling. / Jabbour, Anissa M.; Gordon, Lavinia; Daunt, Carmel P.; Green, Benjamin D.; Kok, Chung H.; D'Andrea, Richard; Ekert, Paul G.
In: PloS one, Vol. 7, No. 2, e31428, 14.02.2012.Research output: Contribution to journal › Article
TY - JOUR
T1 - p53-dependent transcriptional responses to interleukin-3 signaling
AU - Jabbour, Anissa M.
AU - Gordon, Lavinia
AU - Daunt, Carmel P.
AU - Green, Benjamin D.
AU - Kok, Chung H.
AU - D'Andrea, Richard
AU - Ekert, Paul G.
PY - 2012/2/14
Y1 - 2012/2/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84856913593&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0031428
DO - 10.1371/journal.pone.0031428
M3 - Article
VL - 7
JO - PLoS ONE
T2 - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 2
M1 - e31428
ER -