v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization: Alteration of AU-rich element-binding proteins

S. Sobue, M. Murakami, Y. Banno, H. Ito, A. Kimura, S. Gao, A. Furuhata, A. Takagi, T. Kojima, M. Suzuki, Y. Nozawa, T. Murate

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Abstract

Sphingosine kinase 1 (SPHK1) is overexpressed in solid tumors and leukemia. However, the mechanism of SPHK1 overexpression by oncogenes has not been defined. We found that v-Src-transformed NIH3T3 cells showed a high SPHK1 mRNA, SPHK1 protein and SPHK enzyme activity. siRNA of SPHK1 inhibited the growth of v-Src-NIH3T3, suggesting the involvement of SPHK1 in v-Src-induced oncogenesis. v-Src-NIH3T3 showed activations of protein kinase C-α, signal transducers and activators of transcription 3 and c-Jun NH2-terminal kinase. Their inhibition suppressed SPHK1 expression in v-Src-NIH3T3, whereas their overexpression increased SPHK1 mRNA in NIH3T3. Unexpectedly, the nuclear run-on assay and the promoter analysis using 5′-promoter region of mouse SPHK1 did not show any significant difference between mock- and v-Src-NIH3T3. Furthermore, the half-life of SPHK1 mRNA in mock-NIH3T3 was nearly 15 min, whereas that of v-Src-NIH3T3 was much longer. Examination of two AU-rich region-binding proteins, AUF1 and HuR, that regulate mRNA decay reciprocally, showed decreased total AUF1 protein associated with increased tyrosine-phosphorylated form and increased serine-phosphorylated HuR protein in v-Src-NIH3T3. Modulation of AUF1 and HuR by their overexpression or siRNA revealed that SPHK1 mRNA in v-Src- and mock-NIH3T3 was regulated reciprocally by these factors. Our results showed, for the first time, a novel mechanism of v-Src-induced SPHK1 overexpression.

Original languageEnglish
Pages (from-to)6023-6033
Number of pages11
JournalOncogene
Volume27
Issue number46
DOIs
Publication statusPublished - 09-10-2008

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Sobue, S., Murakami, M., Banno, Y., Ito, H., Kimura, A., Gao, S., Furuhata, A., Takagi, A., Kojima, T., Suzuki, M., Nozawa, Y., & Murate, T. (2008). v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization: Alteration of AU-rich element-binding proteins. Oncogene, 27(46), 6023-6033. https://doi.org/10.1038/onc.2008.198