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

S Sobue1, M Murakami, Y Banno

  • 1Department of Medical Technology, Nagoya University Graduate School of Health Sciences, Nagoya, Japan.

Oncogene
|June 25, 2008
PubMed

Insights

Oncogenic v-Src enhances Sphingosine kinase 1 (SPHK1) expression by increasing mRNA stability, not transcription. This involves altered interactions with RNA-binding proteins AUF1 and HuR, revealing a novel oncogenic mechanism.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Sphingosine kinase 1 (SPHK1) is frequently overexpressed in various cancers, including solid tumors and leukemia.
  • The precise mechanisms by which oncogenes drive SPHK1 overexpression remain largely undefined.

Purpose of the Study:

  • To elucidate the mechanism by which the oncogene v-Src induces overexpression of Sphingosine kinase 1 (SPHK1).
  • To investigate the role of SPHK1 in v-Src-mediated oncogenesis.

Main Methods:

  • Utilized v-Src-transformed NIH3T3 cells and mock-transfected controls.
  • Assessed SPHK1 mRNA, protein levels, and enzyme activity.
  • Employed siRNA to inhibit SPHK1 and evaluated cell growth.
  • Investigated signaling pathways including PKC-alpha, STAT3, and JNK.
  • Performed nuclear run-on assays and promoter analysis.
  • Measured SPHK1 mRNA half-life.
  • Examined the roles of RNA-binding proteins AUF1 and HuR.

Main Results:

  • v-Src transformation led to significantly elevated SPHK1 mRNA, protein, and enzyme activity.
  • SPHK1 inhibition impaired the growth of v-Src-transformed cells.
  • Activation of PKC-alpha, STAT3, and JNK pathways was observed in v-Src-NIH3T3 cells.
  • Neither promoter activity nor transcription rates of SPHK1 were altered by v-Src.
  • SPHK1 mRNA exhibited markedly increased stability in v-Src-transformed cells.
  • v-Src altered the phosphorylation status and association of AUF1 and HuR, impacting SPHK1 mRNA decay.

Conclusions:

  • v-Src induces SPHK1 overexpression primarily by enhancing mRNA stability, not transcriptional activity.
  • The oncogenic mechanism involves reciprocal regulation of SPHK1 mRNA by AUF1 and HuR.
  • This study reveals a novel pathway for v-Src-mediated SPHK1 upregulation in cancer development.

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