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Induction and Diagnosis of Tumors in Drosophila Imaginal Disc Epithelia
Published on: July 25, 2017
Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis
Toshiki Itoh1, Sachiyo Iwashita, Michael B Cohen
1Department of Pathology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. toshiki-ito@uiowa.edu
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.
Insights
The DNA Damage-Binding protein 2 (DDB2) is crucial for tumor suppression. DDB2 deficiency in mice shortens lifespan, increases tumor frequency, and impacts apoptosis, highlighting its role in cancer development.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The DNA Damage-Binding (DDB) protein complex, particularly its DDB2 subunit, is known for its role in DNA repair.
- DDB2's involvement in tumor suppressor p53 pathways is suggested but not fully understood.
Purpose of the Study:
- To investigate the in vivo function of DDB2 in relation to lifespan, spontaneous tumor development, and apoptosis.
- To elucidate the interaction between DDB2 and the p53 pathway in a whole-animal model.
Main Methods:
- Generation and analysis of Ddb2 knockout (Ddb2(-/-)) and heterozygous (Ddb2(+/-)) mice.
- Assessment of lifespan, tumor incidence and spectrum, body weight, organ weights, spleen size, testicular germ cell apoptosis, and p53/phospho-p53 levels.
Main Results:
- Ddb2(-/-) and Ddb2(+/-) mice exhibited shortened lifespans and increased spontaneous tumors, notably lung and mammary adenocarcinomas.
- Ddb2 deficiency led to smaller body size, spleen enlargement due to lymphoid proliferation, larger testes, and reduced germ cell apoptosis.
- Reduced p53 levels and serine 15 phosphorylation were observed in testicular germ cells of Ddb2(-/-) mice.
- Tumors in Ddb2(+/-) mice retained wild-type Ddb2 alleles, suggesting haploinsufficiency.
Conclusions:
- DDB2 functions as a tumor suppressor in vivo, regulating apoptosis and tumor incidence.
- DDB2 deficiency impacts multiple physiological processes and predisposes to cancer development.
- Haploinsufficiency of DDB2 can contribute to tumor formation, underscoring its critical role in maintaining genomic stability and preventing cancer.
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