title: Presenilins regulate the cellular level of the tumor suppressor PTEN.
abstract: Alzheimer's Disease (AD) is characterized by amyloid plaques consisting of beta-amyloid (Abeta) peptides and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Abeta is proteolytically derived from its precursor protein through cleavages by beta-secretase and gamma-secretase complex comprising presenilins (PS, PS1/PS2), nicastrin, APH-1 and PEN-2. PS1 is also known to activate the PI3K/Akt cell survival pathway in a gamma-secretase-independent manner. The tumor suppressor PTEN, which antagonizes the PI3K/Akt pathway, has increasingly been recognized to play a key role in neural functions and its level found reduced in AD brains. Here, we demonstrate that the protein level of PTEN is dramatically reduced in cultured cells and embryonic tissues deficient in PS, and in the cortical neurons of PS1/PS2 conditional double knockout mice. Restoration of PS in PS-deficient cells reverses the reduction of PTEN. Regulation of PTEN by PS is independent of the PS/gamma-secretase activity since impaired gamma-secretase by the gamma-secretase inhibitor treatment or due to nicastrin deficiency has little effect on the protein level of PTEN. Our data suggest an important role for PS in signaling pathways involving PI3K/Akt and PTEN that are crucial for physiological functions and the pathogenesis of multiple diseases.
authors.affiliation: Institute for Biomedical Research and School of Life Sciences, Xiamen University, 361005 Xiamen, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.forename: Runzhong
authors.initials: R
authors.lastname: Liu
authors.forename: Ruishan
authors.initials: R
authors.lastname: Wang
authors.forename: Shuigen
authors.initials: S
authors.lastname: Hong
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.forename: Yun-wu
authors.initials: YW
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism*
chemical_list: D053763:Presenilins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse