Point mutation of the ras gene, an event frequently caused in cultured cells by chemical carcinogens, was commonly found in many human tumors. Data indicated that ras mutation is involved in tumor progression. How the mutated ras gene promotes tumor progression is unclear. On the basis of the checkpoint control of the cell cycle and the effects of oncogenic Ras (the protein product of mutated ras gene) on chromatin structures and on the cell cycle, a testable model is proposed to explain how oncogenic Ras promotes tumor progression. In this model, oncogenic Ras permanently activates a 96 kDa histone H2b kinase (p96h2bk), which in turn permanently phosphorylates some chromatin-associated proteins (e.g., histones) to cause chromatin changes (or DNA damage). The chromatin changes then inhibit Cdc2 kinase to arrest the cell cycle. Severe changes in the chromatin (or DNA) lead to a full inhibition of Cdc2 kinase and thus to a complete arrest of the cell cycle. The arrested cells eventually die. However, slight or moderate chromatin changes only partially inhibit the kinase, failing to prevent the cells with damaged DNA from continued cycling. This results in the development of DNA instability and the evolution of tumor cells in the progeny. Experiments are proposed to test this model by determining whether p96h2bk induces chromatin changes and arrests cell-cycle progression in the absence of oncogenic Ras. p96h2bk will be purified, anti-p96fh2bk neutralizing antibody will be prepared, and the full-length cDNA of p96h2bk will be cloned for use in the proposed experiments.
| Huang, Tun-Lan; Pian, Jerry P; Pan, Bin-Tao (2013) Oncogenic Ras suppresses Cdk1 in a complex manner during the incubation of activated Xenopus egg extracts. Arch Biochem Biophys 532:61-72 |
| Pian, Jerry Pinghwa; Huang, Tun-Lan; Tsai, Pei-Chi et al. (2004) A 32 kDa protein--whose phosphorylation correlates with oncogenic Ras-induced cell cycle arrest in activated Xenopus egg extracts--is identified as ribosomal protein S6. J Cell Physiol 201:305-19 |
