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Insulin Receptor Substrate-1, p70S6K, and Cell Size in Transformation and Differentiation of Hemopoietic Cells
Valentinis, Barbara Navarro, Magali Zanocco-Marani, Tommaso Edmonds, Pamela McCormick, Jason Sacchi, Ada Romano, Gaetano Reiss, Krzysztof Baserga, Renato
Valentinis, Barbara
Navarro, Magali
Zanocco-Marani, Tommaso
Edmonds, Pamela
McCormick, Jason
Sacchi, Ada
Romano, Gaetano
Reiss, Krzysztof
Baserga, Renato
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Journal article
Date
2000-08-18
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Biology
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https://doi.org/10.1074/jbc.M002271200
Abstract
After an initial burst of cell proliferation, the type 1 insulin-like growth factor receptor (IGF-IR) induces granulocytic differentiation of 32D IGF-IR cells, an interleukin-3-dependent murine hemopoietic cell line devoid of insulin receptor substrate-1 (IRS-1). The combined expression of the IGF-IR and IRS-1 (32D IGF-IR/IRS-1 cells) inhibits IGF-I-mediated differentiation, and causes malignant transformation of 32D cells. Because of the role of IRS-1 in changing the fate of 32D IGF-IR cells from differentiation (and subsequent cell death) to malignant transformation, we have looked for differences in IGF-IR signaling between 32D IGF-IR and 32D IGF-IR/IRS-1 cells. In this report, we have focused on p70S6K, which is activated by the IRS-1 pathway. We find that the ectopic expression of IRS-1 and the inhibition of differentiation correlated with a sustained activation of p70S6K and an increase in cell size. Phosphorylationin vivo of threonine 389 and, to a lesser extent, of threonine 421/serine 424 of p70S6K seemed to be a requirement for inhibition of differentiation. A role of IRS-1 and p70S6K in the alternative between transformation or differentiation of 32D IGF-IR cells was confirmed by findings that inhibition of p70S6K activation or IRS-1 signaling, by rapamycin or okadaic acid, induced differentiation of 32D IGF-IR/IRS-1 cells. We have also found that the expression of myeloperoxidase mRNA (a marker of differentiation, which sharply increases in 32D IGF-IR cells), does not increase in 32D IGF-IR/IRS-1 cells, suggesting that the expression of IRS-1 in 32D IGF-IR cells causes the extinction of the differentiation program initiated by the IGF-IR, while leaving intact its proliferation program.
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Citation
Barbara Valentinis, Magali Navarro, Tommaso Zanocco-Marani, Pamela Edmonds, Jason McCormick, Andrea Morrione, Ada Sacchi, Gaetano Romano, Krzysztof Reiss, Renato Baserga, Insulin Receptor Substrate-1, p70S6K, and Cell Size in Transformation and Differentiation of Hemopoietic Cells*, Journal of Biological Chemistry, Volume 275, Issue 33, 2000, Pages 25451-25459, ISSN 0021-9258, https://doi.org/10.1074/jbc.M002271200.
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Elsevier
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Journal of Biological Chemistry, Vol. 275, No. 33
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