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Updated: Sep 29, 2026
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Cell lineage-specific effects associated with multiple deficiencies of tumor susceptibility genes in Msh2(-/-)Rb(+/-)
Alexander Yu Nikitin1, Chia-Yang Liu, Andrea Flesken-Nikitin
1Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, TX 78245-3207, USA.
Abstract:
Cooperative effects of genetic alterations are frequently observed during carcinogenesis. Mice carrying germ-line mutations in both Rb and p53 or Msh2 and p53 die earlier of tumors than mice with only one of these genes inactivated. Mice with a single wild-type Rb allele develop a syndrome of multiple neuroendocrine neoplasia, and inactivation of both alleles of Msh2 gene predisposes mice to gastrointestinal cancer, lymphomas and tumors of the skin that exhibit a mismatch repair defect. Here we showed that Msh2(-/-)Rb(+/-) mice developed lymphomas later than Msh2-deficient littermates, and the lymphomas observed in Msh2(-/-)Rb(+/-) mice have increased rates of apoptosis and rarely spread to other organs and tissues. In contrast to lymphomagenesis, courses of neuroendocrine, intestinal, and skin carcinogenesis were not significantly influenced by the Msh2(-/-)Rb(+/-) genetic combination. In these mice, neuroendocrine tumors displayed a loss of the remaining wild-type Rb allele but did not show microsatellite instability. On the other hand, the intestinal and skin tumors exhibited microsatellite instability but kept the remaining wild-type allele of Rb. Taken together, these data not only revealed a novel biological interaction between Rb and Msh2 but also cell lineage specificity effects associated with multiple deficiencies in these tumor susceptibility genes.
Insights
Genetic alterations in Rb and Msh2 genes interact differently across cancer types. While combined deficiencies delayed lymphoma development in mice, other cancers were unaffected, revealing cell-specific effects.
Area of Science:
- Cancer biology
- Genetics
- Tumorigenesis
Background:
- Cooperative genetic alterations accelerate carcinogenesis.
- Germ-line mutations in Rb and p53, or Msh2 and p53, lead to earlier tumor onset.
- Specific gene deficiencies predispose mice to distinct cancer types, such as neuroendocrine neoplasia (Rb) or mismatch repair-deficient tumors (Msh2).
Purpose of the Study:
- To investigate the cooperative effects of Msh2 and Rb gene deficiencies on carcinogenesis.
- To determine the impact of combined Msh2 and Rb inactivation on specific tumor types and their progression.
- To elucidate the biological interaction between Rb and Msh2 in the context of tumor susceptibility.
Main Methods:
- Generation and analysis of Msh2(-/-)Rb(+/-) mice.
- Comparison of tumor development, apoptosis rates, and metastasis in genetically modified mice versus controls.
- Assessment of microsatellite instability and Rb allele status in various tumor types.
Main Results:
- Msh2(-/-)Rb(+/-) mice exhibited delayed lymphoma development compared to Msh2-deficient littermates, with increased apoptosis and reduced metastasis.
- Neuroendocrine tumor development was not significantly influenced by the Msh2(-/-)Rb(+/-) combination, though loss of the wild-type Rb allele occurred without microsatellite instability.
- Intestinal and skin carcinogenesis courses were also unaffected, with tumors showing microsatellite instability but retaining the wild-type Rb allele.
Conclusions:
- A novel biological interaction between Rb and Msh2 was identified, demonstrating cell lineage-specific effects in combined tumor susceptibility gene deficiencies.
- The interplay between Rb and Msh2 influences lymphomagenesis distinctively from neuroendocrine, intestinal, and skin carcinogenesis.
- These findings highlight the complexity of genetic cooperation in cancer development and underscore the importance of cell type in determining gene interaction outcomes.
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