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, Motoshi Suzuki, Y. Nozawa, T. Murate

Research output: Contribution to journalArticle

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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

Fingerprint

AU Rich Elements
src Genes
Oncogene Proteins
Carrier Proteins
Messenger RNA
Small Interfering RNA
sphingosine kinase
STAT3 Transcription Factor
JNK Mitogen-Activated Protein Kinases
RNA Stability
Oncogenes
Genetic Promoter Regions
Serine
Protein Kinase C

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Sobue, S. ; Murakami, M. ; Banno, Y. ; Ito, H. ; Kimura, A. ; Gao, S. ; Furuhata, A. ; Takagi, A. ; Kojima, T. ; Suzuki, Motoshi ; Nozawa, Y. ; Murate, T. / v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization : Alteration of AU-rich element-binding proteins. In: Oncogene. 2008 ; Vol. 27, No. 46. pp. 6023-6033.
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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.",
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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, vol. 27, no. 46, pp. 6023-6033. https://doi.org/10.1038/onc.2008.198

v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization : Alteration of AU-rich element-binding proteins. / Sobue, S.; Murakami, M.; Banno, Y.; Ito, H.; Kimura, A.; Gao, S.; Furuhata, A.; Takagi, A.; Kojima, T.; Suzuki, Motoshi; Nozawa, Y.; Murate, T.

In: Oncogene, Vol. 27, No. 46, 09.10.2008, p. 6023-6033.

Research output: Contribution to journalArticle

TY - JOUR

T1 - v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization

T2 - Alteration of AU-rich element-binding proteins

AU - Sobue, S.

AU - Murakami, M.

AU - Banno, Y.

AU - Ito, H.

AU - Kimura, A.

AU - Gao, S.

AU - Furuhata, A.

AU - Takagi, A.

AU - Kojima, T.

AU - Suzuki, Motoshi

AU - Nozawa, Y.

AU - Murate, T.

PY - 2008/10/9

Y1 - 2008/10/9

N2 - 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.

AB - 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.

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