RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis

Masashi Murakami, Masatoshi Ichihara, Sayaka Sobue, Ryosuke Kikuchi, Hiromi Ito, Ami Kimura, Takashi Iwasaki, Akira Takagi, Tetsuhito Kojima, Masahide Takahashi, Motoshi Suzuki, Yoshiko Banno, Yoshinori Nozawa, Takashi Murate

Research output: Contribution to journalArticle

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Abstract

RET, the receptor of glial cell line-derived neurotrophic factor (GDNF) family ligands, is important for the development of kidney and peripheral neurons. GDNF promotes survival and differentiation of neurons. Mutation of RET leads to the constitutive signal activation causing papillary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). In this study, we report that GDNF/RET signaling up-regulates sphingosine kinase (SPHK) enzyme activity, SPHK1 protein and SPHK1 message in TGW human neuroblastoma cells. Silencing of SPHK1 using siRNA inhibited GDNF-induced neurite formation, GAP43 expression, and cell growth, suggesting the important role of SPHK1 in GDNF signal transduction. Furthermore, NIH3T3 cells transfected with MEN2A type mutated RET but not c-RET demonstrated the up-regulation of SPHK activity, SPHK1 protein and SPHK1 message compared with NIH3T3 cells. The cell growth and anchorage-independent colony formation of MEN2A-NIH3T3 was inhibited with siRNA of SPHK1, while no effect of scramble siRNA was observed. These results suggest the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that activator protein 2 and specificity protein 1 binding motif of the 5′ promoter region of SPHK1 gene is important for its induction by GDNF. Furthermore, we demonstrated that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription by using specific inhibitors.

Original languageEnglish
Pages (from-to)1585-1594
Number of pages10
JournalJournal of Neurochemistry
Volume102
Issue number5
DOIs
Publication statusPublished - 01-09-2007
Externally publishedYes

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Multiple Endocrine Neoplasia Type 2a
Glial Cell Line-Derived Neurotrophic Factor
Gene expression
Carcinogenesis
Gene Expression
Small Interfering RNA
Cell growth
Neurons
Proteins
Up-Regulation
Glial Cell Line-Derived Neurotrophic Factor Receptors
Signal transduction
Mitogen-Activated Protein Kinase 3
Enzyme activity
Neurites
Transcription
Growth
Neuroblastoma
Phosphatidylinositol 3-Kinases
Genetic Promoter Regions

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Murakami, Masashi ; Ichihara, Masatoshi ; Sobue, Sayaka ; Kikuchi, Ryosuke ; Ito, Hiromi ; Kimura, Ami ; Iwasaki, Takashi ; Takagi, Akira ; Kojima, Tetsuhito ; Takahashi, Masahide ; Suzuki, Motoshi ; Banno, Yoshiko ; Nozawa, Yoshinori ; Murate, Takashi. / RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis. In: Journal of Neurochemistry. 2007 ; Vol. 102, No. 5. pp. 1585-1594.
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title = "RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis",
abstract = "RET, the receptor of glial cell line-derived neurotrophic factor (GDNF) family ligands, is important for the development of kidney and peripheral neurons. GDNF promotes survival and differentiation of neurons. Mutation of RET leads to the constitutive signal activation causing papillary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). In this study, we report that GDNF/RET signaling up-regulates sphingosine kinase (SPHK) enzyme activity, SPHK1 protein and SPHK1 message in TGW human neuroblastoma cells. Silencing of SPHK1 using siRNA inhibited GDNF-induced neurite formation, GAP43 expression, and cell growth, suggesting the important role of SPHK1 in GDNF signal transduction. Furthermore, NIH3T3 cells transfected with MEN2A type mutated RET but not c-RET demonstrated the up-regulation of SPHK activity, SPHK1 protein and SPHK1 message compared with NIH3T3 cells. The cell growth and anchorage-independent colony formation of MEN2A-NIH3T3 was inhibited with siRNA of SPHK1, while no effect of scramble siRNA was observed. These results suggest the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that activator protein 2 and specificity protein 1 binding motif of the 5′ promoter region of SPHK1 gene is important for its induction by GDNF. Furthermore, we demonstrated that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription by using specific inhibitors.",
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Murakami, M, Ichihara, M, Sobue, S, Kikuchi, R, Ito, H, Kimura, A, Iwasaki, T, Takagi, A, Kojima, T, Takahashi, M, Suzuki, M, Banno, Y, Nozawa, Y & Murate, T 2007, 'RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis', Journal of Neurochemistry, vol. 102, no. 5, pp. 1585-1594. https://doi.org/10.1111/j.1471-4159.2007.04673.x

RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis. / Murakami, Masashi; Ichihara, Masatoshi; Sobue, Sayaka; Kikuchi, Ryosuke; Ito, Hiromi; Kimura, Ami; Iwasaki, Takashi; Takagi, Akira; Kojima, Tetsuhito; Takahashi, Masahide; Suzuki, Motoshi; Banno, Yoshiko; Nozawa, Yoshinori; Murate, Takashi.

In: Journal of Neurochemistry, Vol. 102, No. 5, 01.09.2007, p. 1585-1594.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis

AU - Murakami, Masashi

AU - Ichihara, Masatoshi

AU - Sobue, Sayaka

AU - Kikuchi, Ryosuke

AU - Ito, Hiromi

AU - Kimura, Ami

AU - Iwasaki, Takashi

AU - Takagi, Akira

AU - Kojima, Tetsuhito

AU - Takahashi, Masahide

AU - Suzuki, Motoshi

AU - Banno, Yoshiko

AU - Nozawa, Yoshinori

AU - Murate, Takashi

PY - 2007/9/1

Y1 - 2007/9/1

N2 - RET, the receptor of glial cell line-derived neurotrophic factor (GDNF) family ligands, is important for the development of kidney and peripheral neurons. GDNF promotes survival and differentiation of neurons. Mutation of RET leads to the constitutive signal activation causing papillary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). In this study, we report that GDNF/RET signaling up-regulates sphingosine kinase (SPHK) enzyme activity, SPHK1 protein and SPHK1 message in TGW human neuroblastoma cells. Silencing of SPHK1 using siRNA inhibited GDNF-induced neurite formation, GAP43 expression, and cell growth, suggesting the important role of SPHK1 in GDNF signal transduction. Furthermore, NIH3T3 cells transfected with MEN2A type mutated RET but not c-RET demonstrated the up-regulation of SPHK activity, SPHK1 protein and SPHK1 message compared with NIH3T3 cells. The cell growth and anchorage-independent colony formation of MEN2A-NIH3T3 was inhibited with siRNA of SPHK1, while no effect of scramble siRNA was observed. These results suggest the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that activator protein 2 and specificity protein 1 binding motif of the 5′ promoter region of SPHK1 gene is important for its induction by GDNF. Furthermore, we demonstrated that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription by using specific inhibitors.

AB - RET, the receptor of glial cell line-derived neurotrophic factor (GDNF) family ligands, is important for the development of kidney and peripheral neurons. GDNF promotes survival and differentiation of neurons. Mutation of RET leads to the constitutive signal activation causing papillary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). In this study, we report that GDNF/RET signaling up-regulates sphingosine kinase (SPHK) enzyme activity, SPHK1 protein and SPHK1 message in TGW human neuroblastoma cells. Silencing of SPHK1 using siRNA inhibited GDNF-induced neurite formation, GAP43 expression, and cell growth, suggesting the important role of SPHK1 in GDNF signal transduction. Furthermore, NIH3T3 cells transfected with MEN2A type mutated RET but not c-RET demonstrated the up-regulation of SPHK activity, SPHK1 protein and SPHK1 message compared with NIH3T3 cells. The cell growth and anchorage-independent colony formation of MEN2A-NIH3T3 was inhibited with siRNA of SPHK1, while no effect of scramble siRNA was observed. These results suggest the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that activator protein 2 and specificity protein 1 binding motif of the 5′ promoter region of SPHK1 gene is important for its induction by GDNF. Furthermore, we demonstrated that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription by using specific inhibitors.

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