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PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells

Oncogene volume 21, pages 5289–5300 (2002)Cite this article

Abstract

Expression of PTENtumor suppressor gene has been known to dephosphorylate the phosphatidylinositol 3´ kinase (PI3K) products on the 3 prime inositol ring, resulting in reduced Akt activation. Loss of PTEN expression in OPM2 and Δ47 human myeloma lines led to high Akt activity toward insulin-like growth factor I (IGF-I). In contrast, mouse plasma cell tumor (PCT) lines, expressing wild type PTEN, did not respond to IGF-I for Akt activation. We demonstrated here that endogenous PTEN played a negative role in controlling Akt activity in both mouse PCT and NIH3T3 fibroblast lines by using anti-sense oligonucleotides against PTEN. To determine the role of src-homology 2-containing inositol 5´ phosphatase (SHIP) in regulating the PI3K/Akt pathway, we manipulated its expression by down-regulation and overexpression in myeloma, PCT and NIH3T3 lines and analysed Akt activation. Our results showed that SHIP, unlike PTEN, did not affect Akt activity in all systems analysed, despite its ability to dephosphorylate a PI3K product. Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity. Biologically, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apoptosis in OPM2 myeloma line. Together, our results have established the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and in myeloma leukemogenesis.

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  1. Yong Choi and Jie Zhang: The first two authors contributed equally to this work

Authors and Affiliations

  1. Lomabardi Cancer Center, Georgetown University Medical Center, Washington, District of Colombia, USA

    Yong Choi, Jie Zhang, Hong Yu & Weiqun Li

  2. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Maryland, USA

    Cristina Murga & J Silvio Gutkind

  3. ISIS Pharmaceuticals, Incorporated, California, USA

    Erich Koller & Brett P Monia

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  1. Yong Choi
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  2. Jie Zhang
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Correspondence to Weiqun Li.

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Choi, Y., Zhang, J., Murga, C. et al. PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. Oncogene 21, 5289–5300 (2002). https://doi.org/10.1038/sj.onc.1205650

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