Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription
The familial Alzheimer's disease gene product beta-amyloid (Abeta) precursor protein (APP) is processed by the beta- and gamma-secretases to produce Abeta as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. AID was originally shown to lower the...
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| Veröffentlicht in: | The Journal of biological chemistry 2002-11, Vol.277 (46), p.44195-44201 |
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| container_title | The Journal of biological chemistry |
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| creator | Scheinfeld, Meir H Ghersi, Enrico Laky, Karen Fowlkes, B J D'Adamio, Luciano |
| description | The familial Alzheimer's disease gene product beta-amyloid (Abeta) precursor protein (APP) is processed by the beta- and gamma-secretases to produce Abeta as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, beta-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the gamma-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. Considering that only APP and not the APLPs have been linked to familial Alzheimer's disease (AD), this data should help in understanding the physiologic roles of the APP family members and in differentiating these functions from the pathologic role of APP in Alzheimer's disease. |
| doi_str_mv | 10.1074/jbc.M208110200 |
| format | Article |
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AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, beta-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the gamma-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. 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AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, beta-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the gamma-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. Considering that only APP and not the APLPs have been linked to familial Alzheimer's disease (AD), this data should help in understanding the physiologic roles of the APP family members and in differentiating these functions from the pathologic role of APP in Alzheimer's disease.</description><subject>Alzheimer Disease - metabolism</subject><subject>Amino Acid Motifs</subject><subject>Amyloid beta-Protein Precursor - analogs & derivatives</subject><subject>Amyloid beta-Protein Precursor - chemistry</subject><subject>Amyloid beta-Protein Precursor - metabolism</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases</subject><subject>Blotting, Western</subject><subject>Brain - metabolism</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Cell Nucleus - metabolism</subject><subject>Cells, Cultured</subject><subject>Cytoplasm - metabolism</subject><subject>Endopeptidases - metabolism</subject><subject>Glutathione Transferase - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Luciferases - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microscopy, Fluorescence</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Point Mutation</subject><subject>Precipitin Tests</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Receptors, Notch</subject><subject>Transcription, Genetic</subject><subject>Transcriptional Activation</subject><subject>Tyrosine - metabolism</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkDtPAzEQhF2ASAi0lMgVnYMf9yxRBAEpCAqoT_Z6L3K4Owf7rsi_xyiRss1qpZnRzkfIneBLwcvscWdg-S55JQSXnF-QOedSsFrm1Yxcx7jjabJaXJGZkFJWUqk5wc_gAWN0w5b6lhocNdP9ofPO0n1AmEL0gXXuB9PpR3QDE1QPljJJzYFudd9rFhFCMkakAbdTp0eMdAx6iBDcfnR-uCGXre4i3p72gny_PH-tXtnmY_22etowUEqMDITUFpQubdkKiQJFDsjzorapk8pr1YIyYExmiqytOdg6y43OKgSwvC6MWpCHY2769XfCODa9i4Bdpwf0U2xKWZR5XsokXB6FEHyMAdtmH1yvw6ERvPmH2SSYzRlmMtyfkifToz3LTyTVHyuNc8o</recordid><startdate>20021115</startdate><enddate>20021115</enddate><creator>Scheinfeld, Meir H</creator><creator>Ghersi, Enrico</creator><creator>Laky, Karen</creator><creator>Fowlkes, B J</creator><creator>D'Adamio, Luciano</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20021115</creationdate><title>Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription</title><author>Scheinfeld, Meir H ; Ghersi, Enrico ; Laky, Karen ; Fowlkes, B J ; D'Adamio, Luciano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-c12adc3a7d7f12e1e15ce0569d8113593fc3bcbb4b64f90cd945ba48eccd096b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Alzheimer Disease - metabolism</topic><topic>Amino Acid Motifs</topic><topic>Amyloid beta-Protein Precursor - analogs & derivatives</topic><topic>Amyloid beta-Protein Precursor - chemistry</topic><topic>Amyloid beta-Protein Precursor - metabolism</topic><topic>Amyloid Precursor Protein Secretases</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases</topic><topic>Blotting, Western</topic><topic>Brain - metabolism</topic><topic>Cell Differentiation</topic><topic>Cell Line</topic><topic>Cell Nucleus - metabolism</topic><topic>Cells, Cultured</topic><topic>Cytoplasm - metabolism</topic><topic>Endopeptidases - metabolism</topic><topic>Glutathione Transferase - metabolism</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Luciferases - metabolism</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microscopy, Fluorescence</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Point Mutation</topic><topic>Precipitin Tests</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Receptors, Notch</topic><topic>Transcription, Genetic</topic><topic>Transcriptional Activation</topic><topic>Tyrosine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Scheinfeld, Meir H</creatorcontrib><creatorcontrib>Ghersi, Enrico</creatorcontrib><creatorcontrib>Laky, Karen</creatorcontrib><creatorcontrib>Fowlkes, B J</creatorcontrib><creatorcontrib>D'Adamio, Luciano</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Scheinfeld, Meir H</au><au>Ghersi, Enrico</au><au>Laky, Karen</au><au>Fowlkes, B J</au><au>D'Adamio, Luciano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-11-15</date><risdate>2002</risdate><volume>277</volume><issue>46</issue><spage>44195</spage><epage>44201</epage><pages>44195-44201</pages><issn>0021-9258</issn><abstract>The familial Alzheimer's disease gene product beta-amyloid (Abeta) precursor protein (APP) is processed by the beta- and gamma-secretases to produce Abeta as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, beta-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the gamma-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. Considering that only APP and not the APLPs have been linked to familial Alzheimer's disease (AD), this data should help in understanding the physiologic roles of the APP family members and in differentiating these functions from the pathologic role of APP in Alzheimer's disease.</abstract><cop>United States</cop><pmid>12228233</pmid><doi>10.1074/jbc.M208110200</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alzheimer Disease - metabolism Amino Acid Motifs Amyloid beta-Protein Precursor - analogs & derivatives Amyloid beta-Protein Precursor - chemistry Amyloid beta-Protein Precursor - metabolism Amyloid Precursor Protein Secretases Animals Aspartic Acid Endopeptidases Blotting, Western Brain - metabolism Cell Differentiation Cell Line Cell Nucleus - metabolism Cells, Cultured Cytoplasm - metabolism Endopeptidases - metabolism Glutathione Transferase - metabolism Humans Immunohistochemistry Luciferases - metabolism Membrane Proteins - metabolism Mice Mice, Knockout Microscopy, Fluorescence Nerve Tissue Proteins - metabolism Point Mutation Precipitin Tests Protein Binding Protein Structure, Tertiary Receptors, Notch Transcription, Genetic Transcriptional Activation Tyrosine - metabolism |
| title | Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription |
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