Uncontrolled Cell Cycle Research Articles

Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control.

Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers. However, the molecular defects underlying this trait, and whether they are a cause or a consequence of the malignant phenotype, are not clear. Mutations that disable the retinoblastoma (Rb) pathway are also common in human cancers. These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression. We show that the mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects. Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis. Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects. These results demonstrate how chromosome instability can arise as a by-product of defects in cell cycle control that compromise the accuracy of mitosis, and suggest a new model to explain the frequent appearance of aneuploidy in human cancer.

４‐ｎｉｔｒｏｑｕｉｎｏｌｉｎｅ １‐ｏｘｉｄｅ誘発ラット舌癌発生過程における細胞動態とＰ型カドヘリンとの関連

The mechanism of carcinogenesis induced by 4-nitroquinoline 1-oxide remains poorly understood.We studied cell kinetics (BrdU, cyclin D 1) and immunohistochemically examined the relation to the cell cycle and morphogenesis (P-cadherin) to determine the mechanism of carcinogenesis. P-cadherin is a cell adhesion molecular essential for morphogenesis. It also has an important role in cell proliferation. However, the role of P-cadherin in carcinogenesis remains unclear.During the epithelial dysplasia stage of carcinogenesis, BrdU and cyclin D 1 were overexpressed significantly as compared with normal epithelial tissue (p=0.0005). The localization of cyclin D 1 and Pcadherin extended from the basal cells to the spinous cell layer. This localization of cyclin D 1 indicated that cells in the spinous cell layer were in the G 1 phase of their cell cycle. P-cadherin simultaneously appeared on their cell membrane.Our results suggest that overexpression of P-cadherin is closely related to the G 1 phase of the cell cycle and that carcinogenesis is induced by an uncontrolled cell cycle with overexpression of P-cadherin.

Differential phosphorylation of lamin B 2 in normal and leukemic cells

Lamins constitute the nuclear lamina, which underlie the inner membrane of the cell nucleus. Phosphorylation of lamins is a key factor in the regulation of nuclear structure during the cell cycle and of gene transcription. Since an uncontrolled cell cycle and altered gene transcription are major characteristics of neoplasms, we looked for differences in lamin B 2 phosphorylation between PBMC, ALL and AML cells. Using different lamin B 2-specific antibodies, we detected two different lamin B 2 species termed lamin B 2 and B 2A. Although phosphorylation of lamin B 2 in leukemic cells was reminiscent of resting cells, the majority of ALL and AML samples showed significantly higher and more altered lamin B 2A phosphorylation compared to PBMC. It remains to be elucidated which mechanism leads to these alterations and whether it could explain the extended G 1-phase frequently observed in ALL cells.