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Titolo:
Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development
Autore:
Smits, R; Kielman, MF; Breukel, C; Zurcher, C; Neufeld, K; Jagmohan-Changur, S; Hofland, N; van Dijk, J; White, R; Edelmann, W; Kucherlapati, R; Khan, PM; Fodde, R;
Indirizzi:
Leidenetherlands Ctr, Dept Human Genet, Ctr Genet Med, NL-2300 RA Leiden, N Leiden Univ Leiden Netherlands NL-2300 RA enet Med, NL-2300 RA Leiden, N Univ Utrecht, Dept Vet Pathol, Utrecht, Netherlands Univ Utrecht UtrechtNetherlands Dept Vet Pathol, Utrecht, Netherlands Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA Univ Utah Salt Lake City UT USA 84112 Inst, Salt Lake City, UT 84112 USA Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med Bronx NY USA 10461 nx, NY 10461 USA Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med Bronx NY USA 10461 nx, NY 10461 USA
Titolo Testata:
GENES & DEVELOPMENT
fascicolo: 10, volume: 13, anno: 1999,
pagine: 1309 - 1321
SICI:
0890-9369(19990515)13:10<1309:AAMMDC>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR-SUPPRESSOR PROTEIN; APC GENE-PRODUCT; MULTIPLE INTESTINAL NEOPLASIA; CENTRAL-NERVOUS-SYSTEM; BETA-CATENIN; COLORECTAL TUMORIGENESIS; FUNCTIONAL INTERACTION; HUMAN HOMOLOG; WILD-TYPE; MUTATIONS;
Keywords:
tumorigenesis; beta-catenin; SAMP; Apc; development;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
64
Recensione:
Indirizzi per estratti:
Indirizzo: Fodde, R Leidenetherlands Ctr, Dept Human Genet, Ctr Genet Med, NL-2300 RALeiden, N Leiden Univ Leiden Netherlands NL-2300 RA NL-2300 RA Leiden, N
Citazione:
R. Smits et al., "Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development", GENE DEV, 13(10), 1999, pp. 1309-1321

Abstract

The adenomatous polyposis coli (APC) gene is considered as the true gatekeeper of colonic epithelial proliferation: It is mutated in the majority of colorectal tumors, and mutations occur at early stages of tumor developmentin mouse and man. These mutant proteins lack most of the seven 20-amino-acid repeats and all SAMP motifs that have been associated with down-regulation of intracellular beta-catenin levels. In addition, they lack the carboxy-terminal domains that bind to DLG, EB1, and microtubulin. APC also appearsto be essential in development because homozygosity for mouse Ape mutations invariably results in early embryonic lethality. Here, we describe the generation of a mouse model carrying a targeted mutation at codon 1638 of themouse Ape gene, Apc1638T, resulting in a truncated Ape protein encompassing three of the seven 20 amino acid repeats and one SAMP motif, but missing all of the carboxy-terminal domains thought to be associated with tumorigenesis. Surprisingly, homozygosity for the Apc1638T mutation is compatible with postnatal life. However, homozygous mutant animals are characterized by growth retardation, a reduced postnatal viability on the B6 genetic background, the absence of preputial glands, and the formation of nipple-associated cysts. Most importantly, Apc(1638T/1638T) animals that survive to adulthood are tumor free. Although the full complement of Apc1638T is sufficient for proper beta-catenin signaling, dosage reductions of the truncated protein result in increasingly severe defects in beta-catenin regulation. The SAMP motif retained in Apc1638T also appears to be important for this functionas shown by analysis of the Apc1572T protein in which its targeted deletion results in a further reduction in the ability of properly controlling beta-catenin/Tcf signaling. These results indicate that the association with DLG, EB1, and microtubulin is less critical for the maintenance of homeostasis by APC than has been suggested previously, and that proper beta-catenin regulation by APC appears to be required for normal embryonic development and tumor suppression.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/12/20 alle ore 05:32:47