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Molecular regulation of gonadotropin receptor expression: relationship to sterol metabolism

K M J Menon1, B Menon, L Wang

  • 1Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI 48109-0617, United States. kmjmenon@umich.edu

Molecular and Cellular Endocrinology
|June 24, 2010
PubMed

Insights

A newly identified protein, mevalonate kinase, binds to LHR mRNA and triggers its degradation. This discovery links ovarian LHR expression regulation to cholesterol metabolism via a post-transcriptional mechanism.

Area of Science:

  • Reproductive Endocrinology
  • Molecular Biology
  • Biochemistry

Background:

  • Luteinizing hormone receptor (LHR) expression is crucial for ovarian function.
  • LHR mRNA levels decrease after LH surges or pharmacological LH/hCG administration.
  • The mechanisms regulating LHR mRNA stability are not fully understood.

Purpose of the Study:

  • To identify proteins that bind to LHR mRNA and regulate its degradation.
  • To elucidate the role of such proteins in LHR downregulation.
  • To investigate the link between LHR expression and cholesterol metabolism.

Main Methods:

  • Purification and identification of LHR mRNA binding proteins.
  • Functional assays using cultured luteal cells treated with 25-hydroxycholesterol.
  • Analysis of mevalonate kinase crystal structure and site-directed mutagenesis.
  • Investigation of ribonucleoprotein (RNP) complex formation and mRNA degradation.

Main Results:

  • A specific LHR mRNA binding protein (LRBP) was identified as mevalonate kinase.
  • Mevalonate kinase selectively binds to a polypyrimidine-rich sequence in LHR mRNA, accelerating its degradation.
  • Abolishing mevalonate kinase expression abrogated LH-induced LHR mRNA downregulation.
  • Mevalonate kinase acts as a translational suppressor, forming an untranslatable RNP complex targeted for degradation.

Conclusions:

  • Mevalonate kinase is a key regulator of LHR mRNA stability and expression in the ovary.
  • LHR expression is controlled by a post-transcriptional mechanism involving mevalonate kinase.
  • This finding establishes a novel link between ovarian LHR regulation and cholesterol biosynthesis.

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