Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL: Cooperation of akt with raf/erk leads to p65 nuclear factor kB-mediated antiapoptosis involving c-IAP2

Vasily M. Gelfanov, Gem S. Burgess, Sara Litz-Jackson, Alastair J. King, Mark S. Marshall, Harikrishna Nakshatri, H. Boswell

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Abstract

Tyrosine kinase oncogenes such as p210BCR-ABL activate multiple signal pathways. As a result, it is difficult to infer the functional relevance of a pathway acting alone or in cooperation with another. One or 2 second-tier kinases represented in the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells. IL-3-dependent cells served, independently, as recipients of p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including raf/erk and akt, respectively, en route to transformation. By contrast, neither RafCAAX nor gag-akt when expressed in parental cells in isolation produced factor-independent cells. On the other hand, H7 cells expressing both RafCAAX and gagakt (H7gag-akt/RafCAAX) were transformed. Such transformation in H7gag-akt/RafCAAX was accomplished in the absence of active versions of Shc or cbl, and there was no evidence of Stat activity and only modest amounts of bcl-xL, a Stat5 transcriptional target protein, all of which characterized the cells transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly increased p65 nuclear factor KB (NFκB) activity. Treatment of cells with a specific NFκB inhibitor, parthenolide, led to loss of NFκB activity and down-regulation of antiapoptotic c-IAP2. In cells with only gag-akt/ RafCAAX, this was sufficient to allow polyADP ribosyltransferase (PARP)-degradative apoptosis, but in cells with p210BCR-ABL, apoptosis was blocked, possibly by a Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic antiapoptotic program, among others, available to certain tyrosine kinase oncogenes involves a cooperative response between raf/erk and akt, unambiguous components of p21ras and PI-3-kinase pathways, to induce p65 NFKB and c-IAP2. (Blood. 2001;98:2508-2517)

Original languageEnglish
Pages (from-to)2508-2517
Number of pages10
JournalBlood
Volume98
Issue number8
DOIs
StatePublished - Oct 15 2001

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Phosphatidylinositol 3-Kinase
Interleukin-3
Protein-Tyrosine Kinases
Cells
Apoptosis
Blood
Phosphotransferases
Oncogenes
Cell Separation
Proteins
Myeloid Cells
Cultured Cells
Signal Transduction
Down-Regulation

ASJC Scopus subject areas

  • Hematology

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Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL : Cooperation of akt with raf/erk leads to p65 nuclear factor kB-mediated antiapoptosis involving c-IAP2. / Gelfanov, Vasily M.; Burgess, Gem S.; Litz-Jackson, Sara; King, Alastair J.; Marshall, Mark S.; Nakshatri, Harikrishna; Boswell, H.

In: Blood, Vol. 98, No. 8, 15.10.2001, p. 2508-2517.

Research output: Contribution to journalArticle

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abstract = "Tyrosine kinase oncogenes such as p210BCR-ABL activate multiple signal pathways. As a result, it is difficult to infer the functional relevance of a pathway acting alone or in cooperation with another. One or 2 second-tier kinases represented in the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells. IL-3-dependent cells served, independently, as recipients of p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including raf/erk and akt, respectively, en route to transformation. By contrast, neither RafCAAX nor gag-akt when expressed in parental cells in isolation produced factor-independent cells. On the other hand, H7 cells expressing both RafCAAX and gagakt (H7gag-akt/RafCAAX) were transformed. Such transformation in H7gag-akt/RafCAAX was accomplished in the absence of active versions of Shc or cbl, and there was no evidence of Stat activity and only modest amounts of bcl-xL, a Stat5 transcriptional target protein, all of which characterized the cells transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly increased p65 nuclear factor KB (NFκB) activity. Treatment of cells with a specific NFκB inhibitor, parthenolide, led to loss of NFκB activity and down-regulation of antiapoptotic c-IAP2. In cells with only gag-akt/ RafCAAX, this was sufficient to allow polyADP ribosyltransferase (PARP)-degradative apoptosis, but in cells with p210BCR-ABL, apoptosis was blocked, possibly by a Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic antiapoptotic program, among others, available to certain tyrosine kinase oncogenes involves a cooperative response between raf/erk and akt, unambiguous components of p21ras and PI-3-kinase pathways, to induce p65 NFKB and c-IAP2. (Blood. 2001;98:2508-2517)",
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AU - Gelfanov, Vasily M.

AU - Burgess, Gem S.

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AU - Nakshatri, Harikrishna

AU - Boswell, H.

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N2 - Tyrosine kinase oncogenes such as p210BCR-ABL activate multiple signal pathways. As a result, it is difficult to infer the functional relevance of a pathway acting alone or in cooperation with another. One or 2 second-tier kinases represented in the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells. IL-3-dependent cells served, independently, as recipients of p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including raf/erk and akt, respectively, en route to transformation. By contrast, neither RafCAAX nor gag-akt when expressed in parental cells in isolation produced factor-independent cells. On the other hand, H7 cells expressing both RafCAAX and gagakt (H7gag-akt/RafCAAX) were transformed. Such transformation in H7gag-akt/RafCAAX was accomplished in the absence of active versions of Shc or cbl, and there was no evidence of Stat activity and only modest amounts of bcl-xL, a Stat5 transcriptional target protein, all of which characterized the cells transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly increased p65 nuclear factor KB (NFκB) activity. Treatment of cells with a specific NFκB inhibitor, parthenolide, led to loss of NFκB activity and down-regulation of antiapoptotic c-IAP2. In cells with only gag-akt/ RafCAAX, this was sufficient to allow polyADP ribosyltransferase (PARP)-degradative apoptosis, but in cells with p210BCR-ABL, apoptosis was blocked, possibly by a Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic antiapoptotic program, among others, available to certain tyrosine kinase oncogenes involves a cooperative response between raf/erk and akt, unambiguous components of p21ras and PI-3-kinase pathways, to induce p65 NFKB and c-IAP2. (Blood. 2001;98:2508-2517)

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