TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival

Yuka Toyoshima, Michael Karas, Shoshana Yakar, Joelle Dupont, Lee Helman, Derek LeRoith

Research output: Contribution to journalArticle

Abstract

Insulin-like growth factor-I (IGF-I) receptors and insulin receptors belong to the same subfamily of receptor tyrosine kinases and share a similar set of intracellular signaling pathways, despite their distinct biological actions. In the present study, we evaluated T cell death-associated gene 51 (TDAG51), which we previously identified by cDNA microarray analysis as a gene specifically induced by IGF-I. We characterized the signaling pathways by which IGF-I induces TDAG51 gene expression and the functional role of TDAG51 in IGF-I signaling in NIH-3T3 (NWTb3) cells, which overexpress the human IGF-I receptor. Treatment with IGF-I increased TDAG51 mRNA and protein levels in NWTb3 cells. This effect of IGF-I was specifically mediated by the IGF-IR, because IGF-I did not induce TDAG51 expression in NIH-3T3 cells overexpressing a dominant-negative IGF-I receptor. Through the use of specific inhibitors of various protein kinases, we found that IGF-I induced TDAG51 expression via the p38 MAPK pathway. The ERK, JNK, and phosphatidylinositol 3-kinase pathways were not involved in IGF-I-induced regulation of TDAG51. To assess the role of TDAG51 in IGF-I signaling, we used small interfering RNA (siRNA) expression vectors directed at two different target sites to reduce the level of TDAG51 protein. In cells expressing these siRNA vectors, TDAG51 protein levels were decreased by 75-80%. Furthermore, TDAG51 siRNA expression abolished the ability of IGF-I to rescue cells from serum starvation-induced apoptosis. These findings suggest that TDAG51 plays an important role in the anti-apoptotic effects of IGF-I.

Original languageEnglish (US)
Pages (from-to)25898-25904
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number24
DOIs
StatePublished - Jun 11 2004

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T-cells
Cell death
Insulin-Like Growth Factor I
Cell Survival
Cell Death
Genes
Cells
T-Lymphocytes
IGF Type 1 Receptor
Gene expression
Small Interfering RNA
NIH 3T3 Cells
Gene Expression
Phosphatidylinositol 3-Kinase
Proteins
Insulin Receptor
Receptor Protein-Tyrosine Kinases
p38 Mitogen-Activated Protein Kinases
Microarray Analysis
Protein Kinase Inhibitors

ASJC Scopus subject areas

  • Biochemistry

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TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival. / Toyoshima, Yuka; Karas, Michael; Yakar, Shoshana; Dupont, Joelle; Helman, Lee; LeRoith, Derek.

In: Journal of Biological Chemistry, Vol. 279, No. 24, 11.06.2004, p. 25898-25904.

Research output: Contribution to journalArticle

Toyoshima, Yuka ; Karas, Michael ; Yakar, Shoshana ; Dupont, Joelle ; Helman, Lee ; LeRoith, Derek. / TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 24. pp. 25898-25904.
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