AMYLOID PRECURSOR PROTEIN MESSENGER-RNA STABILITY IS CONTROLLED BY A 29-BASE ELEMENT IN THE 3'-UNTRANSLATED REGION

In the accompanying paper (Zaidi, S. H. E., Denman, R., and Malter, J. S. (1994) J. Biol. Chem. 269, 24000-24006) we demonstrate that in tum or and normal cells, multiple cytosolic proteins interact with a 29-ba se sequence in the 3'-untranslated region of amyloid precursor protein (APP) mRNA. These data suggested that APP gene expression may be modu lated by regulated APP mRNA decay. We have investigated this predictio n by measuring the decay rates of APP mRNA in resting and mitogen-trea ted peripheral blood mononuclear cells and H4 and K562 tumor cell line s. In resting peripheral blood mononuclear cells, APP mRNA decayed wit h a half-life of 4 h. Under these conditions, the activity of APP mRNA -binding proteins was not detectable. After activation, binding protei n activities were induced, and APP mRNA decay was blocked with a half- life of >12 h. In log phase neuronal or lymphoid tumor cell lines, bin ding activity was constitutively present and APP mRNA displayed a half -life of >12 h. Protein synthesis inhibition by cycloheximide had no e ffect on APP mRNA decay in normal or tumor cells. Transfected wild typ e or mutant APP mRNAs that lacked the 29-base region were stable (t(1/ 2) > 10 h) in K562 tumor cells. Therefore, we conclude that the 29-bas e region functions in cis to destabilize APP mRNA in resting, normal c ells. Upon activation APP mRNA-binding proteins are induced, interact with the 29-base region, and likely participate in stabilization of th e mRNA.