Alternative initiation of translation accounts for a 67/45 kDa dimorphism of the human estrogen receptor ERalpha.
The estrogen receptor protein, in the nuclear receptor superfamily, carries two transactivator domains designated AF1 and AF2. The activity of AF2, localized in the carboxy-terminal region, is ligand-dependent, whereas AF1 (amino-terminal) seems to be activated via the MAPKkinase pathway. Uterine and mammary cells exhibiting large amounts of ERalpha were the first estrogen target organs demonstrated. The response intensity in these tissues is related to the affinity of the receptor and to the number of sites occupied by its ligand. Certain physiological and pharmacological phenomena of estrogen resistance associated with a truncated form of ERalpha (deleted in the AF1 domain) would seem however to challenge this assertion. The 45 kDa truncated form is unable to induce cell proliferation but can still increase the expression of certain genes. In this work we suggest that this 45 kDa ERalpha form may originate from differential regulation of translation of the mRNA encoding the ERalpha. In vitro translation studies and transient expression in COS-7 cells in vivo demonstrated a mechanism of translation regulation that produced from a given mRNA either the wild type ER 67 kDa form or the AF1 deleted ER 45 kDa isoform. Bicistronic vectors were used to demonstrate that the 45 kDa protein originates from translation initiation at AUG 174 induced by an internal ribosome entry.
Barraille
P
P
INSERM U397, Institut Louis Bugnard, CHU Rangueil, Toulouse cedex 4, 31403, France.
Chinestra
P
P
Bayard
F
F
Faye
J C
JC
D020121:5' Untranslated Regions / Q000737:chemistry / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D018387:Codon, Initiator / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics; D047628:Estrogen Receptor alpha; D005260:Female; D005786:Gene Expression Regulation; D005796:Genes / Q000235:genetics; D006801:Humans; D008970:Molecular Weight; D009154:Mutation; D009690:Nucleic Acid Conformation; D016366:Open Reading Frames / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D014162:Transfection
D020121:5' Untranslated Regions; D018387:Codon, Initiator; D018388:Codon, Terminator; D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D011960:Receptors, Estrogen