Cell lineage-specific effects associated with multiple deficiencies of tumor susceptibility genes in Msh2(-/-)Rb(+/-) mice.
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.
Nikitin
Alexander Yu
AY
Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, TX 78245-3207, USA.
Liu
Chia-Yang
CY
Flesken-Nikitin
Andrea
A
Chen
Chi-Fen
CF
Chen
Phang-Lang
PL
Lee
Wen-Hwa
WH
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020137:Base Pair Mismatch / Q000235:genetics; D019070:Cell Lineage; D004268:DNA-Binding Proteins; D005770:Gastrointestinal Neoplasms / Q000235:genetics; D016161:Genes, Retinoblastoma / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000502:physiology; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018895:Microsatellite Repeats / Q000235:genetics; D051718:MutS Homolog 2 Protein; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein