Alternative initiation of translation accounts for a 67/45 kDa dimorphism of the human estrogen receptor ER alpha

The estrogen receptor protein, in the nuclear receptor superfamily, carries two transactivator domains designated AFT and AF2. The activity of AF2, lo calized in the carboxy-terminal region, is ligand-dependent, whereas AF1 (a mino-terminal) seems to be activated via the MAPKkinase pathway. Uterine an d mammary cells exhibiting large amounts of ER alpha were the first estroge n target organs demonstrated. The response intensity in these tissues is re lated to the affinity of the receptor and to the number of sites occupied b y its ligand, Certain physiological and pharmacological phenomena of estrog en resistance associated with a truncated form of ERa! (deleted in the AF1 domain) would seem however to challenge this assertion. The 45 kDa truncate d form is unable to induce cell proliferation but can still increase the ex pression of certain genes, In this work we suggest that this 45 kDa ER alph a! form may originate from differential regulation of translation of the mR NA encoding the ER alpha. In vitro translation studies and transient expres sion in COS-7 cells in vivo demonstrated a mechanism of translation regulat ion 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 demonst rate that the 45 kDa protein originates from translation initiation at AUG 174 induced by an internal ribosome entry. (C) 1999 Academic Press.