Nature Cell Biology：发现可抑制乳腺癌转移蛋白质

日本筑波大学一个研究小组发现，人体细胞中的蛋白质“CHIP”可以抑制乳腺癌细胞增殖和转移。这一成果2月9日发表在英国《自然—细胞生物学》（Nature Cell Biology）杂志网络版上。
研究人员说，他们注意到，在人体细胞中，蛋白质“CHIP”的水平随着乳腺癌的发展而降低，用实验鼠进一步研究发现，减少“CHIP”的量，实验鼠乳腺癌细胞形成大块肿瘤，且转移加快；增加“CHIP”的量，乳腺癌细胞增殖和转移能力则受到极大的抑制。
研究人员说，这一发现表明，可以通过提高“CHIP”蛋白质的量或促使其活跃来抑制乳腺癌细胞的增殖和转移。这项成果为开发防治乳腺癌新药提供了思路。
此外，由于“CHIP”蛋白质也存在于乳腺以外的组织，研究人员推测，它可能还能抑制其他癌症细胞的增殖和转移。（生物谷Bioon.com）
生物谷推荐原始出处：
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.