Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis

Toshiki Itoh; Sachiyo Iwashita; Michael B Cohen; David K Meyerholz; Stuart Linn

doi:10.1093/hmg/ddm107

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Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis

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Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis

Toshiki Itoh, Sachiyo Iwashita, Michael B Cohen, David K Meyerholz and Stuart Linn

Human molecular genetics, Vol.16(13), pp.1578-1586

07/01/2007

DOI: 10.1093/hmg/ddm107

PMID: 17468495

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Abstract

Damage-specific DNA-binding (DDB) protein heterodimer has been extensively studied in the context of nucleotide excision repair. However, the smaller subunit, DDB2, is also implicated in tumor suppressor p53-mediated processes, although the precise details of the DDB2 − p53 interactions are unknown. Here, we report that Ddb2 −/− and Ddb2 +/− mice have shortened lifespans and increased frequency and spectrum of spontaneous tumors. Notably, Ddb2 deficiency enhances lung and mammary adenocarcinomas. Ddb2 −/− mice are smaller than normal. Whereas weights of kidneys and livers are reduced proportionately, spleens from Ddb2 −/− mice gradually enlarge with age due to lymphoid proliferation. Ddb2 −/− mice also have larger testes, and the testicular germ cells show significantly decreased spontaneous apoptosis. These changes parallel reduced levels of p53 and its serine 15 phosphorylation in testicular germ cells. Since tumors that appeared in heterozygous Ddb2 +/− mice conserve the wild-type Ddb2 allele, Ddb2 RNA expression and Ddb2 exon sequence, Ddb2 heterozygosity can facilitate tumor development as a haploinsufficient tumor suppressor. These results demonstrate that in whole animals as in cultured cells Ddb2 can regulate apoptosis and tumor incidence.

Details

Title: Subtitle: Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis
Creators: Toshiki Itoh - 1 Department of Pathology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA and
Sachiyo Iwashita - 1 Department of Pathology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA and
Michael B Cohen - 1 Department of Pathology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA and
David K Meyerholz - 1 Department of Pathology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA and
Stuart Linn - 2 Department of Molecular and Cell Biology, University of California, Barker Hall, Berkeley, CA 94720, USA
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.16(13), pp.1578-1586
DOI: 10.1093/hmg/ddm107
PMID: 17468495
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: Oxford University Press
Language: English
Date published: 07/01/2007
Academic Unit: Pathology
Record Identifier: 9984083817702771

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