Thrombopoietin-induced conformational change in p53 lies downstream of the p44/p42 mitogen activated protein kinase cascade in the human growth factor-dependent cell line M07e

Alec Ritchie, Stephen E. Braun, Johnny He, Hal Broxmeyer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Thrombopoietin is a cytokine with potent megakaryocytopoietic and thrombopoietic activities in vivo. Wild-type p53 is a conformationally flexible, anti-oncogenic transcription factor that plays a principal role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. We recently reported that Tpo induces a conformational change in and functional inactivation of p53, coincident with its anti-apoptotic effects, in the human factor-dependent cell line M07e. In an effort to identify potential signaling cascades through which Tpo illicits these effects on p53, we report here that treating M07e cells with MAPK kinase inhibitor PD98059 dramatically suppressed Tpo-induced conformational change in p53 as well as Tpo-enhanced viability in M07e cells in a p53-dependent manner. Furthermore, the expression of constitutively active Raf1 in M07e cells induced conformational change in p53 independent of Tpo stimulation. Inhibition of the JAK/STAT pathway revealed that JAK/STAT signaling plays an insignificant role in conformational modulation of p53 and apoptosis suppression. Inhibition of phosphatidylinositol-3 kinase did not have a significant effect on p53 conformation but did have a weak but significant effect on Tpo-enhanced viability. Cytokine-induced activation of the MAPK pathway and the subsequent functional neutralization of p53, may be an event which apoptosis is commonly suppressed in hematopoiesis.

Original languageEnglish (US)
Pages (from-to)1465-1477
Number of pages13
JournalOncogene
Volume18
Issue number7
StatePublished - Feb 18 1999

Fingerprint

Thrombopoietin
Mitogen-Activated Protein Kinase 1
Intercellular Signaling Peptides and Proteins
Cell Line
Apoptosis
Phosphatidylinositol 3-Kinase
Cytokines
Mitogen-Activated Protein Kinase Kinases
Hematopoiesis
Transcription Factors

Keywords

  • Apoptosis
  • M07e
  • MAPK
  • p53 conformation
  • Thrombopoietin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Thrombopoietin-induced conformational change in p53 lies downstream of the p44/p42 mitogen activated protein kinase cascade in the human growth factor-dependent cell line M07e. / Ritchie, Alec; Braun, Stephen E.; He, Johnny; Broxmeyer, Hal.

In: Oncogene, Vol. 18, No. 7, 18.02.1999, p. 1465-1477.

Research output: Contribution to journalArticle

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abstract = "Thrombopoietin is a cytokine with potent megakaryocytopoietic and thrombopoietic activities in vivo. Wild-type p53 is a conformationally flexible, anti-oncogenic transcription factor that plays a principal role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. We recently reported that Tpo induces a conformational change in and functional inactivation of p53, coincident with its anti-apoptotic effects, in the human factor-dependent cell line M07e. In an effort to identify potential signaling cascades through which Tpo illicits these effects on p53, we report here that treating M07e cells with MAPK kinase inhibitor PD98059 dramatically suppressed Tpo-induced conformational change in p53 as well as Tpo-enhanced viability in M07e cells in a p53-dependent manner. Furthermore, the expression of constitutively active Raf1 in M07e cells induced conformational change in p53 independent of Tpo stimulation. Inhibition of the JAK/STAT pathway revealed that JAK/STAT signaling plays an insignificant role in conformational modulation of p53 and apoptosis suppression. Inhibition of phosphatidylinositol-3 kinase did not have a significant effect on p53 conformation but did have a weak but significant effect on Tpo-enhanced viability. Cytokine-induced activation of the MAPK pathway and the subsequent functional neutralization of p53, may be an event which apoptosis is commonly suppressed in hematopoiesis.",
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N2 - Thrombopoietin is a cytokine with potent megakaryocytopoietic and thrombopoietic activities in vivo. Wild-type p53 is a conformationally flexible, anti-oncogenic transcription factor that plays a principal role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. We recently reported that Tpo induces a conformational change in and functional inactivation of p53, coincident with its anti-apoptotic effects, in the human factor-dependent cell line M07e. In an effort to identify potential signaling cascades through which Tpo illicits these effects on p53, we report here that treating M07e cells with MAPK kinase inhibitor PD98059 dramatically suppressed Tpo-induced conformational change in p53 as well as Tpo-enhanced viability in M07e cells in a p53-dependent manner. Furthermore, the expression of constitutively active Raf1 in M07e cells induced conformational change in p53 independent of Tpo stimulation. Inhibition of the JAK/STAT pathway revealed that JAK/STAT signaling plays an insignificant role in conformational modulation of p53 and apoptosis suppression. Inhibition of phosphatidylinositol-3 kinase did not have a significant effect on p53 conformation but did have a weak but significant effect on Tpo-enhanced viability. Cytokine-induced activation of the MAPK pathway and the subsequent functional neutralization of p53, may be an event which apoptosis is commonly suppressed in hematopoiesis.

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