最新研究表明,，細胞衰老（細胞周期停滯的一種不可逆形式）在體外可阻止腫瘤生長?，F(xiàn)在,，Hui-Kuan Lin等人識別出一個以前人們不知道的通道，它能驅(qū)動衰老,，但不需要大多數(shù)已知衰老調(diào)控因子的參與,，而是通過轉(zhuǎn)錄因子ATF6以及依賴于細胞周期蛋白的激酶抑制因子p27 和 p21來傳遞信號。這個通道是通過使原致癌基因Skp2失去活性而被發(fā)現(xiàn)的,，但只能是在致癌信號作用的背景下進行,。
在藥理上以Skp2復(fù)合物為目標(biāo)，可通過誘導(dǎo)細胞衰老而限制腫瘤生成,，說明這樣的藥物在癌癥預(yù)防和治療方面也許會有效,。(生物谷Bioon.com)
生物谷推薦原文出處：
Nature doi:10.1038/nature08815
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Hui-Kuan Lin1,2,3, Zhenbang Chen1,2,4,6, Guocan Wang1,2,4,7, Caterina Nardella1,2,4,7, Szu-Wei Lee3,7, Chan-Hsin Chan3, Wei-Lei Yang3, Jing Wang3, Ainara Egia4, Keiichi I. Nakayama5, Carlos Cordon-Cardo2,6, Julie Teruya-Feldstein2 & Pier Paolo Pandolfi1,2,4
1 Cancer Biology and Genetics Program,
2 Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
3 Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
4 Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA
5 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
6 Present addresses: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr D. B. Todd Jr Boulevard, Nashville, Tennessee 37208-3599, USA (Z.C.); Irving Cancer Research Center, Room 309, 1130 St. Nicholas Avenue, New York, New York 10032, USA (C.C.-C.).
7 These authors contribute equally to this work.
Correspondence to: Pier Paolo Pandolfi1,2,4 Correspondence and requests for materials should be addressed to P.P.P. (Email: [email protected]).
Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19Arf–p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19Arf–p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf–p53 response is impaired, whereas a Skp2–SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.
