High frequency of development of B cell lymphoproliferation and diffuse large B cell lymphoma in Dbl knock-in mice.
In: Journal of Molecular Medicine, Jg. 89 (2011-05-01), Heft 5, S. 493-504
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Zugriff:
Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho, Rac, and Cdc42 and to induce a transformed phenotype in murine fibroblasts. We previously reported that Dbl-null mice are viable and fertile but display defective dendrite elongation of distinct subpopulations of cortical neurons, suggesting a role of Dbl in controlling dendritic growth. To gain deeper insights into the role of Dbl in development and disease, we attempted a knock-in approach to create an endogenous allele that encodes a missense-mutation-mediated loss of function in the DH domain. We generated, by gene targeting technology, a mutant mouse strain by inserting a mutagenized human proto-Dbl cDNA clone expressing only the Dbl N terminus regulatory sequence at the starting codon of murine exon 1. Animals were monitored over a 21-month period, and necropsy specimens were collected for histological examination and immunohistochemistry analysis. Dbl knock-in mice are viable and did not manifest either decreased reproductive performances or gross developmental phenotype but revealed a reduced lifespan compared to wild-type (w.t.) mice and showed, with aging, a B cell lymphoproliferation that often has features of a frank diffuse large B cell lymphoma. Moreover, Dbl knock-in male mice displayed an increased incidence of lung adenoma compared to w.t. mice. These data indicate that Dbl is a tumor susceptibility gene in mice and that loss of function of Dbl DH domain by genetic missense mutations is responsible for induction of diffuse large B cell lymphoma. [ABSTRACT FROM AUTHOR]
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High frequency of development of B cell lymphoproliferation and diffuse large B cell lymphoma in Dbl knock-in mice.
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Autor/in / Beteiligte Person: | Ognibene, Marzia ; Barbieri, Ottavia ; Vanni, Cristina ; Mastracci, Luca ; Astigiano, Simonetta ; Emionite, Laura ; Salani, Barbara ; Fedele, Manuela ; Resaz, Roberta ; Tenca, Claudya ; Fais, Franco ; Sabatini, Federica ; De Santanna, Amleto ; Altruda, Fiorella ; Varesio, Luigi ; Hirsch, Emilio ; Eva, Alessandra |
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Zeitschrift: | Journal of Molecular Medicine, Jg. 89 (2011-05-01), Heft 5, S. 493-504 |
Veröffentlichung: | 2011 |
Medientyp: | academicJournal |
ISSN: | 0946-2716 (print) |
DOI: | 10.1007/s00109-010-0712-4 |
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