TAILIEUCHUNG - Báo cáo khoa học: Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases Retinoic acid-induced upregulation of substrate and proteinase ADAM10 during neuronal cell differentiation

Cleavage of the amyloid precursor protein (APP) within the amyloid-beta (Ab) sequence by the a-secretase prevents the formation of toxic Abpep-tides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17) act asa-secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsa. | iFEBS Journal Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases Retinoic acid-induced upregulation of substrate and proteinase ADAM10 during neuronal cell differentiation Kristina Endres1 Rolf Postina1 Anja Schroeder2 Ulrike Mueller3 and Falk Fahrenholz1 1 Institute of Biochemistry Johannes Gutenberg-University Mainz Germany 2 ZVTE Johannes Gutenberg-University Mainz Germany 3 Institute for Pharmacia and Molecular Biotechnology University of Heidelberg Germany Keywords ADAM10 Alzheimer s disease amyloid precursor protein-like protein 2 retinoic acid tumor necrosis factor-a converting enzyme Correspondence F. Fahrenholz Institute of Biochemistry Johannes Gutenberg-University Becherweg 30 D-55128 Mainz Germany E-mail Received 27 June 2005 revised 14 September 2005 accepted 16 September 2005 doi Cleavage of the amyloid precursor protein APP within the amyloid-beta Ab sequence by the a-secretase prevents the formation of toxic Ap peptides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE ADAM17 act as a-secretases and stimulate the generation of a soluble neuroprotective fragment of APP APPsa. Here we demonstrate that the related APP-like protein 2 APLP2 which has been shown to be essential for development and survival of mice is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma cells was observed with an ADAM10-preferring inhibitor. Transgenic mice with neuron-specific overexpression of ADAM10 showed significantly increased levels of soluble APLP2 and its C-terminal fragments. To elucidate a possible regulatory mechanism of APLP2 shedding in the neuronal context we examined retinoic acid-induced differentiation of neuroblastoma cells. Retinoic acid treatment of two .

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