L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation

Activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

Hung Yun Lin, Mingzeng Sun, Heng Yuan Tang, Cassie Lin, Mary K. Luidens, Shaker A. Mousa, Sandra Incerpi, George L. Drusano, Faith B. Davis, Paul J. Davis

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

3,5,3′-Triiodo-L-thyronine (T 3), but not L-thyroxine (T 4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an α vβ 3 integrin receptor on human glioblastoma U-87 MG cells. Although both T 3 and T 4 stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T 3-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T 3 and T 4. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T 3-treated U-87 MG cells. T 3 and T 4 both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T 3 on U-87 MG cells. PI3-kinase-dependent actions of T 3 in these cells included shuttling of nuclear thyroid hormone receptor-α (TRα) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1α mRNA; LY-294002 inhibited these actions. Results of studies involving α vβ 3 receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T 3 from the integrin by unlabeled T 3 and by unlabeled T 4, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T 3 exclusively, activates PI3-kinase via Src kinase, and stimulates TRα trafficking and HIF-1α gene expression. Tetrac and RGD peptide both inhibit T 3 action at this site. The second site binds T 4 and T 3, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T 3 action here is inhibited by tetrac alone, but the effect of T 4 is blocked by both tetrac and the RGD peptide.

Original languageEnglish
Pages (from-to)C980-C991
JournalAmerican Journal of Physiology - Cell Physiology
Volume296
Issue number5
DOIs
Publication statusPublished - May 2009
Externally publishedYes

Fingerprint

Thyronines
Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinases
Thyroxine
Cell Proliferation
src-Family Kinases
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Integrins
Hypoxia-Inducible Factor 1
Thyroid Hormone Receptors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Glioblastoma
Cytoplasmic and Nuclear Receptors
Small Interfering RNA
Cytoplasm
Gene Expression
Messenger RNA
tetraiodothyroacetic acid

Keywords

  • Extracellular signal-regulated kinase 1/2
  • Glioblastoma cells
  • Integrin α β
  • Intracellular hormone receptor trafficking
  • Mitogen-activated protein kinase
  • Phosphatidylinositol 3-kinase
  • Src kinase
  • Thyroid hormone

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation : Activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. / Lin, Hung Yun; Sun, Mingzeng; Tang, Heng Yuan; Lin, Cassie; Luidens, Mary K.; Mousa, Shaker A.; Incerpi, Sandra; Drusano, George L.; Davis, Faith B.; Davis, Paul J.

In: American Journal of Physiology - Cell Physiology, Vol. 296, No. 5, 05.2009, p. C980-C991.

Research output: Contribution to journalArticle

Lin, Hung Yun ; Sun, Mingzeng ; Tang, Heng Yuan ; Lin, Cassie ; Luidens, Mary K. ; Mousa, Shaker A. ; Incerpi, Sandra ; Drusano, George L. ; Davis, Faith B. ; Davis, Paul J. / L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation : Activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. In: American Journal of Physiology - Cell Physiology. 2009 ; Vol. 296, No. 5. pp. C980-C991.
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abstract = "3,5,3′-Triiodo-L-thyronine (T 3), but not L-thyroxine (T 4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an α vβ 3 integrin receptor on human glioblastoma U-87 MG cells. Although both T 3 and T 4 stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T 3-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T 3 and T 4. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T 3-treated U-87 MG cells. T 3 and T 4 both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T 3 on U-87 MG cells. PI3-kinase-dependent actions of T 3 in these cells included shuttling of nuclear thyroid hormone receptor-α (TRα) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1α mRNA; LY-294002 inhibited these actions. Results of studies involving α vβ 3 receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T 3 from the integrin by unlabeled T 3 and by unlabeled T 4, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T 3 exclusively, activates PI3-kinase via Src kinase, and stimulates TRα trafficking and HIF-1α gene expression. Tetrac and RGD peptide both inhibit T 3 action at this site. The second site binds T 4 and T 3, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T 3 action here is inhibited by tetrac alone, but the effect of T 4 is blocked by both tetrac and the RGD peptide.",
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T2 - Activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

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AU - Sun, Mingzeng

AU - Tang, Heng Yuan

AU - Lin, Cassie

AU - Luidens, Mary K.

AU - Mousa, Shaker A.

AU - Incerpi, Sandra

AU - Drusano, George L.

AU - Davis, Faith B.

AU - Davis, Paul J.

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KW - Integrin α β

KW - Intracellular hormone receptor trafficking

KW - Mitogen-activated protein kinase

KW - Phosphatidylinositol 3-kinase

KW - Src kinase

KW - Thyroid hormone

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