Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53.
The exact duplication of chromosomal DNA during each cell cycle ensures the correct inheritance of genetic material from mother to daughter cells. In eukaryotic cells, DNA replication can occur only when the origin of DNA replication is accurately marked by a group of proteins termed licensing proteins. One such protein is Cdt1, which is recruited first to the origin of DNA replication followed by cell division cycle 6 (Cdc6) and mini-chromosome maintenance proteins (Mcms). We previously reported that NIH3T3 cells overexpressing Cdt1 readily formed tumors in mice. To further investigate its oncogenic mechanism, we generated transgenic mice expressing Cdt1 in thymocytes. Our studies demonstrated that T-cell-directed Cdt1 transgenic mice showed normal T-cell development. However, such transgenic mice developed thymic lymphoblastic lymphoma when crossed with p53 null mice. Furthermore, tumor cells derived from NIH3T3 cells overexpressing Cdt1 displayed numerical and structural chromosomal aberrations in the form of ploidy, double minutes, translocation, inversion, chromosome end-to-end fusion and robertsonian mutation. Collectively, our studies suggest that Cdt1 overexpression most likely contributes to tumorigenecity by causing genomic instability.
Seo
Junghee
J
Department of Pathology and Immunology, Washington University School of Medicine, Suwon, Korea.
Chung
Yun S
YS
Sharma
Girdhar G
GG
Moon
Eunpyo
E
Burack
Walter R
WR
Pandita
Tej K
TK
Choi
Kyunghee
K
D000375:Aging; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D019382:Human Growth Hormone / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D019382:Human Growth Hormone