Molecular regulation of gonadotropin receptor expression: relationship to sterol metabolism.
We have identified a specific LHR mRNA binding protein that selectively binds to the polypyrimidine-rich bipartite sequence in the coding region of the LHR mRNA and accelerates its degradation. This process has been shown to be one of the mechanisms that is responsible for the loss of the steady-state levels of LHR mRNA following the preovulatory LH surge or the down regulation of the receptor in response to the administration of a pharmacological dose of LH or hCG. The trans factor, designated as the LHR mRNA binding protein (LRBP), was purified and its identity was established as being mevalonate kinase, an enzyme involved in cholesterol biosynthesis. When mevalonate kinase expression was abolished by treating cultured luteal cells with 25-hydroxycholesterol, the ability to undergo LH-induced down regulation of LHR mRNA was completely abrogated. Examination of the crystal structure of mevalonate kinase coupled with mutagenesis of the critical residues in the catalytic site revealed that the catalytic site is in close proximity to the LHR mRNA binding site. Further studies revealed that mevalonate kinase causes LHR mRNA degradation by acting as a translational suppressor by forming an untranslatable ribonucleoprotein (RNP) complex which is then targeted for degradation. These studies show that LHR expression in the ovary is regulated by a post-transcriptional mechanism mediated by mevalonate kinase thereby linking LHR expression with cholesterol metabolism.
Menon
K M J
KM
Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI 48109-0617, United States. kmjmenon@umich.edu
Menon
B
B
Wang
L
L
Gulappa
T
T
Harada
M
M
D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011967:Receptors, Gonadotropin / Q000235:genetics*; D011974:Receptors, LH / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*
D011967:Receptors, Gonadotropin; D011974:Receptors, LH; D013261:Sterols; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase