日本筑波大學(xué)一個研究小組發(fā)現(xiàn),，人體細(xì)胞中的蛋白質(zhì)“CHIP”可以抑制乳腺癌細(xì)胞增殖和轉(zhuǎn)移,。這一成果2月9日發(fā)表在英國《自然—細(xì)胞生物學(xué)》（Nature Cell Biology）雜志網(wǎng)絡(luò)版上。
研究人員說,，他們注意到,，在人體細(xì)胞中,，蛋白質(zhì)“CHIP”的水平隨著乳腺癌的發(fā)展而降低，用實(shí)驗(yàn)鼠進(jìn)一步研究發(fā)現(xiàn),，減少“CHIP”的量,，實(shí)驗(yàn)鼠乳腺癌細(xì)胞形成大塊腫瘤，且轉(zhuǎn)移加快,；增加“CHIP”的量,，乳腺癌細(xì)胞增殖和轉(zhuǎn)移能力則受到極大的抑制。
研究人員說,，這一發(fā)現(xiàn)表明,，可以通過提高“CHIP”蛋白質(zhì)的量或促使其活躍來抑制乳腺癌細(xì)胞的增殖和轉(zhuǎn)移。這項成果為開發(fā)防治乳腺癌新藥提供了思路,。
此外,，由于“CHIP”蛋白質(zhì)也存在于乳腺以外的組織，研究人員推測,，它可能還能抑制其他癌癥細(xì)胞的增殖和轉(zhuǎn)移,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature Cell Biology Published online: 8 February 2009 | doi:10.1038/ncb1839
The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways
Masashi Kajiro1,6, Ryuichi Hirota1,6, Yuka Nakajima1, Kaori Kawanowa2, Kae So-ma1, Ichiaki Ito1, Yuri Yamaguchi3, Sho-hei Ohie1, Yasuhito Kobayashi2, Yuko Seino3, Miwako Kawano1, Yoh-ichi Kawabe1, Hiroyuki Takei2, Shin-ichi Hayashi4, Masafumi Kurosumi2, Akiko Murayama1,5, Keiji Kimura1 & Junn Yanagisawa1,5
CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs 13, 14, 15, 16, 17, 18, 19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.
1 Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan.
2 Department of Pathology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi- gun, Saitama 362-0806, Japan.
3 Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi- gun, Saitama 362-0806, Japan.
4 Department of Medical Technology, Course of Health Sciences, School of Medicine, Tohoku University, 2-1 Seiryou-machi, Aoba-ku, Sendai, 980-8575, Japan.
5 Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan.
6 These authors contributed equally to this work.
