Estrogen receptor α (ERα) can be phosphorylated at various residues, one of which is serine 212 in the DNA binding domain. The majority of human nuclear receptors conserves, as a motif, this serine residue within their DNA binding domain. Among these nuclear receptors, phosphorylation of the corresponding threonine 38 in the nuclear receptor CAR is essential for determining its activity [9]. Here, we have investigated the role of phosphorylated serine 212 in the regulation of ERα activity by comparing it with serine 236, another potential phosphorylation site within the DNA binding domain, and demonstrated that phosphorylation of serine 212 confers upon ERα a distinct activity regulating gene expression in Huh-7 cells. In Western blot analysis, wild type ERα and mutants ERα S212A, ERα S212D, ERα S236A and ERα S236D were equally expressed in the nucleus, thus indicating that phosphorylation does not determine nuclear localization of ERα. ERα S212D, but not ERα S236D, retained its capability of activating an ERE-reporter gene in luciferase assays. Similar results were also obtained for human ERβ; the ERβ S176D mutant retained its trans-activation activity, but the ERβ S200D mutant did not. cDNA microarray and Ingenuity Pathway Analysis, employed on Huh-7 cells ectopically expressing either ERα S212A or ERα S212D, revealed that phosphorylation of serine 212 enabled ERα to regulate a unique set of genes and cellular functions.
When Guyer & Smith (1918, 1924) subjected pregnant rabbits to active and passive immunization with lens proteins, it was noted that a high percentage of the new-born showed lens anomalies and other ocular changes such as microphthalmia and coloboma of the iris. Though these experiments seem to indicate that antibodies circulating in the maternal circulation may interfere with embryonic development, the results of this work have subsequently been questioned, since neither Finlay (1924), Huxley & Carr-Saunders (1924), nor Flickinger, Levi, & Smith (1955) were able to produce any eye abnormalities with lens antibodies.
Recently, it has again been suggested, that tissue antibodies may cause congenital defects based on antigen-antibody interaction in the developing embryo (Brent, Averich, & Drapiewski, 1961; Gluecksohn-Waelsch, 1957; Miller, 1958; Barber, Willis, & Afeman, 1961).
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