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

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-a, signal transducers and activators of transcription 3 and c-Jun NH 2 -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 0 -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.

Similar Regulation of Human Inducible Nitric-oxide Synthase Expression by Different Isoforms of the RNA-binding Protein AUF1

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Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents

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Characterizing the endoribonuclease activity of APE1.

“…The interactions between mRNAs and RBPs and their subsequent effects on cells seem complex and vary between studied cell lines. Recent report shows overexpression of HuR is directly responsible for the increase of kinase mRNA in fibroblasts (Sobue et al 2008) while another study reports HuR can stabilize tumor suppressor mRNA in prostate cancer cell lines and in anti-cancer therapeutics (Quann et al 2007;Bandyopadhyay et al 2008).…”