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Calcium-induced activation of a mutant G-protein-coupled receptor causes in vitro transformation of NIH/3T3 cells

A O Hoff1, G J Cote, H A Fritsche

  • 1Department of Internal Medicine Specialties, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Neoplasia (New York, N.Y.)
|August 10, 2000
PubMed

Insights

Activating mutations in the calcium-sensing receptor (CaR) promote cell growth and colony formation. This aberrant CaR activation may link to unusual neoplasms in affected families.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • The calcium-sensing receptor (CaR), a G-protein-coupled receptor, is widely expressed and regulates cell growth.
  • Activating CaR mutations cause autosomal dominant hypocalcemia, characterized by low calcium and high urinary calcium levels.
  • A family with an activating CaR mutation (Thr151Met) exhibited hypocalcemia and unusual neoplasms, prompting further investigation.

Purpose of the Study:

  • To investigate the transforming effects of the activating CaR mutation (Thr151Met).
  • To explore the role of the mutant CaR in cellular proliferation and its potential link to neoplastic manifestations.

Main Methods:

  • Transfection of NIH/3T3 cells with normal and mutant CaR.
  • Assessing colony formation in soft agar at varying calcium concentrations.
  • Analyzing the activation of specific signaling pathways (ERK1/2, JNK/SAPK, p38 MAPK) in response to calcium.

Main Results:

  • NIH/3T3 cells expressing the mutant CaR formed colonies in soft agar at subphysiologic calcium levels, unlike cells with the normal receptor.
  • The mutant CaR induced calcium-dependent activation of extracellular signal-regulated protein kinase (ERK) 1/2 and Jun-N-terminal kinase/stress-activated (JNK/SAPK) pathways.
  • Activation of the p38 MAP kinase pathway was not observed.

Conclusions:

  • The mutant CaR possesses transforming properties, promoting cellular proliferation.
  • Aberrant activation of the mutant CaR may contribute to the unusual neoplastic conditions observed in the studied family.
  • These findings highlight the CaR's role in regulating cellular proliferation and its implications in oncogenesis.

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