Abstract
Tyrosine kinase oncoproteins cause simultaneous activation of multiple intracellular signaling pathways. However, the precise mechanisms by which individual pathways induce oncogenesis are not well understood. We have investigated the roles of individual signaling pathways in v-Src-dependent cell growth and survival by inhibiting one particular pathway. v-Src induced constitutive activation of signal transducers and activators of transcription 3 (STAT3), phosphatidylinositol 3-kinase, and Ras in murine Ba/F3 cells and led to factor-independent proliferation. Dominant-negative mutants of STAT3 (STAT3D) and phosphatidylinositol 3-kinase (Deltap85) inhibited v-Src-dependent growth by approximately 60 and approximately 40%, respectively. Moreover, dominant-negative Ras (N17) induced severe apoptosis, which was accompanied by down-regulation of Bcl-2 and activation of caspase-3. Although cells overexpressing Bcl-2 or caspase-3 inhibitors remained viable even when N17 was expressed, the growth was reduced by approximately 85%. During N17- and STAT3D-induced growth suppression, expression of cyclin D2, cyclin D3, c-myc, and c-fos was suppressed by N17, whereas that of cyclin D2, cyclin E, and c-myc was suppressed by STAT3D. Thus, v-Src-activated Ras and STAT3 are involved in distinct but partly overlapping transcriptional regulation of cell cycle regulatory molecules. These results suggest that the full oncogenic activity of v-Src requires simultaneous activation of multiple signalings, in which Ras is particularly required for survival.
Highlights
Tyrosine kinase oncoproteins cause simultaneous activation of multiple intracellular signaling pathways
V-Src-activated Ras and signal transducers and activators of transcription 3 (STAT3) are involved in distinct but partly overlapping transcriptional regulation of cell cycle regulatory molecules. These results suggest that the full oncogenic activity of v-Src requires simultaneous activation of multiple signalings, in which Ras is required for survival
Overexpression of v-Src but Not v-Src⌬SH2 Leads to IL-3independent Growth of Ba/F3 Cells—To analyze the signaling events induced by v-src oncogene, we initially introduced an expression vector of v-src, v-src⌬SH2, which lacked the SH2 domain or an empty control vector into a murine IL-3-dependent cell line Ba/F3
Summary
Ras is profoundly involved in cell survival signals from growth factors because it has been demonstrated that a C-terminal truncated granulocyte-macrophage colony-stimulating factor receptor, which is unable to nase; STAT, signal transducers and activators of transcription; PI3-K, phosphatidylinositol 3-kinase; IL, interleukin; Ab, antibody; PY, phosphotyrosine; IPTG, isopropyl--D-thiogalactopyranoside; TUNEL, terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labeling; LacR, Lac repressor. We inducibly expressed dominant-negative forms of Ras (N17), STAT3 (STAT3D), and PI3-K (⌬p85) in v-Src-transformed Ba/F3 cells and examined their effects on v-Src-induced cell growth and survival in association with the expression and function of cell cycle and apoptosis regulatory molecules
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