Metabolic stabilization of p53 by FE65 in the nuclear matrix of osmotically stressed cells.
FE65 is a neural adaptor protein known to interact with a number of proteins, including Alzheimer's amyloid beta-protein precursor (APP). Although several different functions have been proposed for FE65, its primary physiological role remains unclear. We previously showed that APP can liberate FE65 from the membrane as a result of APP phosphorylation, and that the liberated FE65 translocates into the nuclei of osmotically stressed cells. Within the nucleus, FE65 formed a patched structure at the nuclear matrix, which facilitated the induction of gammaH2AX [Nakaya T, Kawai T & Suzuki T (2008) J Biol Chem283, 19119-19131]. Here, we report that the tumor suppressor p53 is colocalized with FE65 in the nuclear patches and is stabilized by FE65 in sorbitol-treated cells. In FE65 knockdown cells, protein levels of p53 targeted to the nuclear matrix were rapidly decreased through the proteasome degradation pathway after sorbitol treatment, as compared with control cells. These results suggest that the translocation of FE65 to the nuclear matrix, along with the formation of nuclear patches, is required for the stabilization of p53 by its suppression of the proteasome degradation pathway, thus facilitating the subsequent induction of gammaH2AX in osmotically stressed cells.
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Tadashi
T
Nakaya
Tomoko
T
Kawai
Toshiharu
T
Suzuki
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D006657:Histones / Q000096:biosynthesis; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000502:physiology*; D015530:Nuclear Matrix / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology*; D009997:Osmotic Pressure; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D013012:Sorbitol / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D013012:Sorbitol; D046988:Proteasome Endopeptidase Complex