CENP-R acts bilaterally as a tumor suppressor and an oncogene in the two-stage skin carcinogenesis model

Abstract

CENP-R is a component of the CENP-O complex, including CENP-O, CENP-P, CENP-Q, CENP-R, and CENP-U and is constitutively localized to kinetochores throughout the cell cycle in vertebrates. CENP-R deficient chicken DT40 cells are viable and show very minor effect on mitosis. To investigate the functional roles of CENP-R in vivo, we generated CENP-R deficient mice (Cenp-r^-/-). Mice heterozygous or homozygous for Cenp-r null mutation are viable and healthy, with no apparent defect in growth and morphology, indicating Cenp-r is not essential for normal development. Accordingly, to investigate the role of the Cenp-r gene in skin carcinogenesis, we subjected Cenp-r^-/- mice to the DMBA/TPA chemical carcinogenesis protocol and monitored their tumor development. As a result, Cenp-r^-/- mice initially developed significantly more papillomas than control wild type mice. However, papillomas in Cenp-r^-/- mice showed a decrease of proliferative cells and an increase of apoptotic cells. As a result, they did not grow bigger and some papillomas showed substantial regression. Furthermore, papillomas in Cenp-r^-/- mice showed lower frequency of malignant conversion to squamous cell carcinomas. These results indicate Cenp-r functions bilaterally in cancer development: during early developmental stages, Cenp-r behaves as a tumor suppressor, but during the expansion and progression of papillomas it behaves as a tumor-promoting factor.

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