Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation Journal Article
| Authors: | Oki, S.; Limnander, A.; Pin, M. Y.; Niki, M.; Pandolfi, P. P.; Rothman, P. B. |
| Article Title: | Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation |
| Abstract: | The v-Abl tyrosine kinase activates several signaling pathways during transformation of bone marrow cells in mice. Because the SH2-containing inositol 5′-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated. Bone marrow cells from either Dok1- or SHIP-deficient mice are more susceptible to transformation by v-Abl. v-Abl-transformed preB cells from these knockout mice show Abl kinase-dependent hyperproliferation and moderate resistance to apoptosis. Elevated activation of Ras, Raf-1, and Erk, but not of Akt, was observed in either SHIP -/- or Dok1 -/- v-Abl-transformed cells. This activation is sensitive to treatment with STI571. Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP -/- or Dok1 -/- cells in a dose-dependent manner. Complementation of SHIP -/- or Dok1 -/- cells abrogates their hyperproliferation and intracellular Erk activation. These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells. ©2005 Landes Bioscience. |
| Keywords: | signal transduction; protein kinase b; controlled study; leukemia; oncoprotein; dna-binding proteins; raf protein; nonhuman; cell proliferation; animal cell; animals; mice; bone marrow cells; apoptosis; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; mitogen activated protein kinase inhibitor; cell line; mitogenesis; enzyme activation; dose-response relationship, drug; oncogene proteins v-abl; pyrimidines; b lymphocyte; cell transformation, neoplastic; rna-binding proteins; cell transformation; protein farnesyltransferase inhibitor; mitogen activated protein kinase 3; extracellular signal-regulated map kinases; phosphoproteins; bone marrow cell; ras proteins; mouse strain; phosphoric monoester hydrolases; oncogene ras; ras; map kinase kinase 1; map kinase kinase 2; methionine; knockout mouse; virus protein; gene expression regulation, leukemic; erk; farnesyltranstransferase; dok; ship; v-abl; leukemia, pre-b-cell |
| Journal Title: | Cell Cycle |
| Volume: | 4 |
| Issue: | 2 |
| ISSN: | 1538-4101 |
| Publisher: | Taylor & Francis Inc. |
| Date Published: | 2005-02-01 |
| Start Page: | 310 |
| End Page: | 314 |
| Language: | English |
| PUBMED: | 15655368 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 24 October 2012" - "Source: Scopus" |
