Role for PI-3-Kinase in C-MYC expression by P210 BCR-ABL

E. A. Williamen, G. S. Burgess, M. T. Rizzo, S. Litz-Jackson, A. S. Kraft, H. Boswell

Research output: Contribution to journalArticle

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Abstract

Transcription of c-myc is a requirement for hematopoietic transformation by p210 BCR-ABL, product of the Philadelphia chromosome. Additionally, phosphatidyIinositol-3-kinase (PI-3-kinase), has been closely linked to cellular proliferation in hematopoietic systems. Whether the mechanism by which p210 BCR-ABL affects c-myc expression may involve PI-3-kinasc was investigated. By immunoprecipitation, the PI-3-kinase regulatory subunit, p85, was found in a complex with adaptor protein She, previously linked to p2lrus activation in BCRABL transformed cells. Use of specific PI-3-kinase inhibitors, wortmannin (WM) and LY294002, revealed dose-dependent, selective inhibition of c-myc mRNA expression at concentrations that did not affect expression of c-jun mRNA, an endpoint of p21ras activity. A transcriptional basis for downmodulation of c-myc mRNA expression by WM was proved by actinomycin D decay. Neither the cjun regulatory enzyme JNK, nor the ras/raf-dependcnt enzyme, ERK2/MAP kinase, were inhibited by WM, supporting a distinct enzymatic effector pathway for expression of c-myc mRNA compared to c-jun. On the other hand, the dosedependent inhibition of c-myc mRNA expression conformed to the dosedependence of PI-3-kinase inhibition in Bcr-Abl.A54 cells at 100-300 nM. The identity of downstream effector(s) responsible for c-myc transcription, influenced by PI-3-kinase, was investigated. Cyclin-dependent kinase 4 (cdk4) activity for phosphorylating retinoblastoma protein, pRb (ultimately responsible for E2F1dependent c-myc transcription) was highly sensitive to inhibition of PI-3-kinase. The cytosolic enzyme, akt or protein kinase B, was also enzymatically inactivated downstream of PI-3-kinase by WM treatment, suggesting it may represent an intermediate effector of cdk4 regulation sensitive to the intracellular concentration of PIP3, the PI-3-kinase product. Thus, PI-3-kinase regulation of substrate enzyme, akt, and of cdk4, defines a unique pathway for c-myc transcription from p210 BCR-ABL, which diverges from the pathway downstream of p21ras activation by BCR-ABL.

Original languageEnglish (US)
Pages (from-to)1110
Number of pages1
JournalExperimental Hematology
Volume24
Issue number9
StatePublished - 1996
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Phosphotransferases
Cyclin-Dependent Kinase 4
Messenger RNA
Enzymes
Hematopoietic System
Philadelphia Chromosome
Retinoblastoma Protein
Proto-Oncogene Proteins c-akt
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Dactinomycin
Immunoprecipitation
Cell Proliferation
wortmannin

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Williamen, E. A., Burgess, G. S., Rizzo, M. T., Litz-Jackson, S., Kraft, A. S., & Boswell, H. (1996). Role for PI-3-Kinase in C-MYC expression by P210 BCR-ABL. Experimental Hematology, 24(9), 1110.

Role for PI-3-Kinase in C-MYC expression by P210 BCR-ABL. / Williamen, E. A.; Burgess, G. S.; Rizzo, M. T.; Litz-Jackson, S.; Kraft, A. S.; Boswell, H.

In: Experimental Hematology, Vol. 24, No. 9, 1996, p. 1110.

Research output: Contribution to journalArticle

Williamen, EA, Burgess, GS, Rizzo, MT, Litz-Jackson, S, Kraft, AS & Boswell, H 1996, 'Role for PI-3-Kinase in C-MYC expression by P210 BCR-ABL', Experimental Hematology, vol. 24, no. 9, pp. 1110.
Williamen EA, Burgess GS, Rizzo MT, Litz-Jackson S, Kraft AS, Boswell H. Role for PI-3-Kinase in C-MYC expression by P210 BCR-ABL. Experimental Hematology. 1996;24(9):1110.
Williamen, E. A. ; Burgess, G. S. ; Rizzo, M. T. ; Litz-Jackson, S. ; Kraft, A. S. ; Boswell, H. / Role for PI-3-Kinase in C-MYC expression by P210 BCR-ABL. In: Experimental Hematology. 1996 ; Vol. 24, No. 9. pp. 1110.
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abstract = "Transcription of c-myc is a requirement for hematopoietic transformation by p210 BCR-ABL, product of the Philadelphia chromosome. Additionally, phosphatidyIinositol-3-kinase (PI-3-kinase), has been closely linked to cellular proliferation in hematopoietic systems. Whether the mechanism by which p210 BCR-ABL affects c-myc expression may involve PI-3-kinasc was investigated. By immunoprecipitation, the PI-3-kinase regulatory subunit, p85, was found in a complex with adaptor protein She, previously linked to p2lrus activation in BCRABL transformed cells. Use of specific PI-3-kinase inhibitors, wortmannin (WM) and LY294002, revealed dose-dependent, selective inhibition of c-myc mRNA expression at concentrations that did not affect expression of c-jun mRNA, an endpoint of p21ras activity. A transcriptional basis for downmodulation of c-myc mRNA expression by WM was proved by actinomycin D decay. Neither the cjun regulatory enzyme JNK, nor the ras/raf-dependcnt enzyme, ERK2/MAP kinase, were inhibited by WM, supporting a distinct enzymatic effector pathway for expression of c-myc mRNA compared to c-jun. On the other hand, the dosedependent inhibition of c-myc mRNA expression conformed to the dosedependence of PI-3-kinase inhibition in Bcr-Abl.A54 cells at 100-300 nM. The identity of downstream effector(s) responsible for c-myc transcription, influenced by PI-3-kinase, was investigated. Cyclin-dependent kinase 4 (cdk4) activity for phosphorylating retinoblastoma protein, pRb (ultimately responsible for E2F1dependent c-myc transcription) was highly sensitive to inhibition of PI-3-kinase. The cytosolic enzyme, akt or protein kinase B, was also enzymatically inactivated downstream of PI-3-kinase by WM treatment, suggesting it may represent an intermediate effector of cdk4 regulation sensitive to the intracellular concentration of PIP3, the PI-3-kinase product. Thus, PI-3-kinase regulation of substrate enzyme, akt, and of cdk4, defines a unique pathway for c-myc transcription from p210 BCR-ABL, which diverges from the pathway downstream of p21ras activation by BCR-ABL.",
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AU - Williamen, E. A.

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N2 - Transcription of c-myc is a requirement for hematopoietic transformation by p210 BCR-ABL, product of the Philadelphia chromosome. Additionally, phosphatidyIinositol-3-kinase (PI-3-kinase), has been closely linked to cellular proliferation in hematopoietic systems. Whether the mechanism by which p210 BCR-ABL affects c-myc expression may involve PI-3-kinasc was investigated. By immunoprecipitation, the PI-3-kinase regulatory subunit, p85, was found in a complex with adaptor protein She, previously linked to p2lrus activation in BCRABL transformed cells. Use of specific PI-3-kinase inhibitors, wortmannin (WM) and LY294002, revealed dose-dependent, selective inhibition of c-myc mRNA expression at concentrations that did not affect expression of c-jun mRNA, an endpoint of p21ras activity. A transcriptional basis for downmodulation of c-myc mRNA expression by WM was proved by actinomycin D decay. Neither the cjun regulatory enzyme JNK, nor the ras/raf-dependcnt enzyme, ERK2/MAP kinase, were inhibited by WM, supporting a distinct enzymatic effector pathway for expression of c-myc mRNA compared to c-jun. On the other hand, the dosedependent inhibition of c-myc mRNA expression conformed to the dosedependence of PI-3-kinase inhibition in Bcr-Abl.A54 cells at 100-300 nM. The identity of downstream effector(s) responsible for c-myc transcription, influenced by PI-3-kinase, was investigated. Cyclin-dependent kinase 4 (cdk4) activity for phosphorylating retinoblastoma protein, pRb (ultimately responsible for E2F1dependent c-myc transcription) was highly sensitive to inhibition of PI-3-kinase. The cytosolic enzyme, akt or protein kinase B, was also enzymatically inactivated downstream of PI-3-kinase by WM treatment, suggesting it may represent an intermediate effector of cdk4 regulation sensitive to the intracellular concentration of PIP3, the PI-3-kinase product. Thus, PI-3-kinase regulation of substrate enzyme, akt, and of cdk4, defines a unique pathway for c-myc transcription from p210 BCR-ABL, which diverges from the pathway downstream of p21ras activation by BCR-ABL.

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