マツイ　タケシ   Takeshi Matsui   松井　毅    所属   応用生物学部 応用生物学科    職種   教授
言語種別	英語
発行・発表の年月	2021/10
形態種別	学術論文
査読	査読あり
標題	K15 promo-driven enforced expression of NKIRAS exhibits tumor suppressive activity against the development of DMBA/TPA-induced skin tumors
執筆形態	共著
掲載誌名	Scientific Reports
掲載区分	国外
出版社・発行元	SPRINGER NATURE
巻・号・頁	11(1),pp.20658
著者・共著者	Tago K, Ohta S, Aoki-Ohmura C, Funakoshi-Tago M, Sashikawa M, Matsui T, Miyamoto Y, Wada T, Oshio T, Komine M, Matsugi J, Furukawa Y, Ohtsuki M, Yamauchi J, Yanagisawa K
概要	NKIRAS1 and NKIRAS2 (also called as κB‐Ras) were identified as members of the atypical RAS family that suppress the transcription factor NF‐κB. However, their function in carcinogenesis is still controversial. To clarify how NKIRAS acts on cellular transformation, we generated transgenic mice in which NKIRAS2 was forcibly expressed using a cytokeratin 15 (K15) promoter, which is mainly activated in follicle bulge cells. The ectopic expression of NKIRAS2 was mainly detected in follicle bulges of transgenic mice with NKIRAS2 but not in wild type mice. K15 promoter‐driven expression of NKIRAS2 failed to affect the development of epidermis, which was evaluated using the expression of K10, K14, K15 and filaggrin. However, K15 promoter‐driven expression of NKIRAS2 effectively suppressed the development of skin tumors induced by treatment with 7,12‐dimethylbenz(a) anthracene (DMBA)/12‐O‐tetradecanoylphorbol 13‐acetate (TPA). This observation suggested that NKIRAS seemed to function as a tumor suppressor in follicle bulges. However, in the case of oncogenic HRAS‐driven cellular transformation of murine fibroblasts, knockdown of NKIRAS2 expression drastically suppressed HRAS‐mutant‐provoked cellular transformation, suggesting that NKIRAS2 was required for the cellular transformation of murine fibroblasts. Furthermore, moderate enforced expression of NKIRAS2 augmented oncogenic HRAS‐provoked cellular transformation, whereas an excess NKIRAS2 expression converted its functional role into a tumor suppressive phenotype, suggesting that NKIRAS seemed to exhibit a biphasic bell‐shaped enhancing effect on HRAS‐mutant‐ provoked oncogenic activity. Taken together, the functional role of NKIRAS in carcinogenesis is most likely determined by not only cellular context but also its expression level.