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- Publisher Website: 10.1073/pnas.98.4.1859
- Scopus: eid_2-s2.0-0035852788
- PMID: 11172041
- WOS: WOS:000166949200098
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Article: p53 accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101
Title | p53 accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101 |
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Authors | |
Issue Date | 2001 |
Citation | Proceedings of the National Academy of Sciences of the United States of America, 2001, v. 98, n. 4, p. 1859-1864 How to Cite? |
Abstract | Functional inactivation of the tumor susceptibility gene tsg101 in NIH 3T3 fibroblasts results in cellular transformation and the ability to form metastatic tumors in nude mice. The N-terminal region of tsg101 protein is structurally similar to the catalytic domain of ubiquitin-conjugating enzymes, suggesting a potential role of tsg101 in ubiquitin-mediated protein degradation. The C-terminal domain of TSG101 can function as a repressor of transcription. To investigate the physiological function of tsg101, we generated a null mutation of the mouse gene by gene targeting. Homozygous tsg101-/- embryos fail to develop past day 6.5 of embryogenesis (E6.5), are reduced in size, and do not form mesoderm. Mutant embryos show a decrease in cellular proliferation in vivo and in vitro but no increase in apoptosis. Although levels of p53 transcripts were not affected in tsg101-/- embryos, p53 protein accumulated dramatically, implying altered posttranscriptional control of p53. In addition, transcription of the p53 effector, cyclin-dependent kinase inhibitor p21WAF-1/CIP-1, was increased 5- to 10-fold, whereas activation of MDM2 transcription secondary to p53 elevation was not observed. Introduction of a p53 null mutation into tsg101-/- embryos rescued the gastrulation defect and prolonged survival until E8.5. These results demonstrate that tsg101 is essential for the proliferative burst before the onset of gastrulation and establish a functional connection between tsg101 and the p53 pathway in vivo. |
Persistent Identifier | http://hdl.handle.net/10722/291583 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Ruland, Jürgen | - |
dc.contributor.author | Sirard, Christian | - |
dc.contributor.author | Elia, Andrew | - |
dc.contributor.author | MacPherson, David | - |
dc.contributor.author | Wakeham, Andrew | - |
dc.contributor.author | Li, Limin | - |
dc.contributor.author | De La Pompa, José Luis | - |
dc.contributor.author | Cohen, Stanley N. | - |
dc.contributor.author | Mak, Tak W. | - |
dc.date.accessioned | 2020-11-17T14:54:41Z | - |
dc.date.available | 2020-11-17T14:54:41Z | - |
dc.date.issued | 2001 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 2001, v. 98, n. 4, p. 1859-1864 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | http://hdl.handle.net/10722/291583 | - |
dc.description.abstract | Functional inactivation of the tumor susceptibility gene tsg101 in NIH 3T3 fibroblasts results in cellular transformation and the ability to form metastatic tumors in nude mice. The N-terminal region of tsg101 protein is structurally similar to the catalytic domain of ubiquitin-conjugating enzymes, suggesting a potential role of tsg101 in ubiquitin-mediated protein degradation. The C-terminal domain of TSG101 can function as a repressor of transcription. To investigate the physiological function of tsg101, we generated a null mutation of the mouse gene by gene targeting. Homozygous tsg101-/- embryos fail to develop past day 6.5 of embryogenesis (E6.5), are reduced in size, and do not form mesoderm. Mutant embryos show a decrease in cellular proliferation in vivo and in vitro but no increase in apoptosis. Although levels of p53 transcripts were not affected in tsg101-/- embryos, p53 protein accumulated dramatically, implying altered posttranscriptional control of p53. In addition, transcription of the p53 effector, cyclin-dependent kinase inhibitor p21WAF-1/CIP-1, was increased 5- to 10-fold, whereas activation of MDM2 transcription secondary to p53 elevation was not observed. Introduction of a p53 null mutation into tsg101-/- embryos rescued the gastrulation defect and prolonged survival until E8.5. These results demonstrate that tsg101 is essential for the proliferative burst before the onset of gastrulation and establish a functional connection between tsg101 and the p53 pathway in vivo. | - |
dc.language | eng | - |
dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | - |
dc.title | p53 accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101 | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1073/pnas.98.4.1859 | - |
dc.identifier.pmid | 11172041 | - |
dc.identifier.pmcid | PMC29347 | - |
dc.identifier.scopus | eid_2-s2.0-0035852788 | - |
dc.identifier.volume | 98 | - |
dc.identifier.issue | 4 | - |
dc.identifier.spage | 1859 | - |
dc.identifier.epage | 1864 | - |
dc.identifier.isi | WOS:000166949200098 | - |
dc.identifier.issnl | 0027-8424 | - |