The Study Of The Mechanism Of Oncogene RET Rearrangement In Papiilary Thyroid Carcinomas

Children exposed to radioactive iodine after the Chernobyl reactor accident frequently developed papillary thyroid carcinomas (PTC). The predominant molecular lesions in these tumors was rearrangement of the proto-oncogene ret. The RET protein, a receptor tyrosine kinase, played an important role in the development of enteric nervous system and kidney. The ligands of RET have been demonstrated as the glial cell-derived neurotrophic factor (GDNF) family. At present, studies focus on the mechanism of ret gene rearrangement in the early stage and on the role of Ret in development of thyroid cancer.In this study RT-PCR was performed to detect the ret arrangements in some specimens embedded in paraffin of Chinese PTC. Four types of ret rearrangement were found. Among those the frequency of PTC1 was the highest. We also observed that multiple rearrangements co-occurred in some specimen.We also demonstrated that PTC1 protein could directly interact with ATM, a sensor of DNA double-strand breaks, which belongs to the PI3-kinase family. Neither ionizing radiation (IR) nor treatment with wortmannin, the specific inhibitor of PI3K family, could abolish the interaction. Deletion analysis indicated that the binding regions were the LZPR domain of ATM and the TK domain of PTC1. However, the un-rearranged RET protein lost the ability to bind to ATM.Furthermore, we investigated the effect of the interaction on the kinase activity each other. Over expression of ATM-LZPR had no effect on the kinase activity of PTC 1. However, overexpressed PTC1 reduced the activation level of ATM kinase by IR, and, in turn, decreased the phosphorylation level of p53 on the N-terminal Serine 15. The Gl arrest after IR was also attenuated. In addition, overexpressed PTC1 could retain ATM-LZPR in the cytoplasm.Taken together, these results suggested that PTC 1 rearrangement might lead to the disorder of DNA damage and repair, cell cycle checkpoint machinery and impair the cellular homeostasis and maintenance of genome stability via direct interaction with ATM. This contributes to elucidate the precise mechanism of tumorigenesis and development of thyroid cancers.