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

Anissa Jabbour, Carmel Patricia Daunt, Benjamin D Green, Sandra Vogel, Lavinia Gordon, Rachel Szu-Hui Lee, Natasha Silke, Richard Bruce Pearson, Cassandra J Vandenberg, Priscilla Kelly, Stephen L Nutt, Andreas Strasser, Christoph Borner, Paul G Ekert

Research output: Contribution to journalArticleResearchpeer-review

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 p21cip/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.
Original languageEnglish
Pages (from-to)344 - 352
Number of pages9
JournalBlood
Volume115
Issue number2
DOIs
Publication statusPublished - 2010
Externally publishedYes

Cite this

Jabbour, Anissa ; Daunt, Carmel Patricia ; Green, Benjamin D ; Vogel, Sandra ; Gordon, Lavinia ; Lee, Rachel Szu-Hui ; Silke, Natasha ; Pearson, Richard Bruce ; Vandenberg, Cassandra J ; Kelly, Priscilla ; Nutt, Stephen L ; Strasser, Andreas ; Borner, Christoph ; Ekert, Paul G. / Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. In: Blood. 2010 ; Vol. 115, No. 2. pp. 344 - 352.
@article{832dcef6ff5d48b9acf1ae404704c53a,
title = "Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation",
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 p21cip/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.",
author = "Anissa Jabbour and Daunt, {Carmel Patricia} and Green, {Benjamin D} and Sandra Vogel and Lavinia Gordon and Lee, {Rachel Szu-Hui} and Natasha Silke and Pearson, {Richard Bruce} and Vandenberg, {Cassandra J} and Priscilla Kelly and Nutt, {Stephen L} and Andreas Strasser and Christoph Borner and Ekert, {Paul G}",
year = "2010",
doi = "10.1182/blood-2009-07-230730",
language = "English",
volume = "115",
pages = "344 -- 352",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
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Jabbour, A, Daunt, CP, Green, BD, Vogel, S, Gordon, L, Lee, RS-H, Silke, N, Pearson, RB, Vandenberg, CJ, Kelly, P, Nutt, SL, Strasser, A, Borner, C & Ekert, PG 2010, 'Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation' Blood, vol. 115, no. 2, pp. 344 - 352. https://doi.org/10.1182/blood-2009-07-230730

Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. / Jabbour, Anissa; Daunt, Carmel Patricia; Green, Benjamin D; Vogel, Sandra; Gordon, Lavinia; Lee, Rachel Szu-Hui; Silke, Natasha; Pearson, Richard Bruce; Vandenberg, Cassandra J; Kelly, Priscilla; Nutt, Stephen L; Strasser, Andreas; Borner, Christoph; Ekert, Paul G.

In: Blood, Vol. 115, No. 2, 2010, p. 344 - 352.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation

AU - Jabbour, Anissa

AU - Daunt, Carmel Patricia

AU - Green, Benjamin D

AU - Vogel, Sandra

AU - Gordon, Lavinia

AU - Lee, Rachel Szu-Hui

AU - Silke, Natasha

AU - Pearson, Richard Bruce

AU - Vandenberg, Cassandra J

AU - Kelly, Priscilla

AU - Nutt, Stephen L

AU - Strasser, Andreas

AU - Borner, Christoph

AU - Ekert, Paul G

PY - 2010

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N2 - 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 p21cip/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.

AB - 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 p21cip/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.

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