Nature：研究发现RANK蛋白与前列腺或乳腺癌中癌细胞的转移相关

生物谷

生物谷报道：最近一个用小鼠前列腺癌模型所做的实验研究，识别出了刺激转移形成的一个信号通道。当一个蛋白配体占据一个被称为RANK（receptor activator of nuclear factor κ B）的受体时，该通道被激发，并且它还依赖于这种激发和IKKα (IkB kinase a)的核转位。一旦进入细胞核中，被激发的IKKα就会抑制maspin基因转录，该转录的产物已被明确为前列腺癌和乳腺癌中细胞迁移和入侵的一个抑制成分。因此，RANK可能是前列腺癌或乳房肿瘤细胞中都有的转移行为的一个促进剂（启动子）。该研究成果被发表于4月5日出版的《自然》杂志上。

FIGURE 1. IKK activity is required for prostate cancer metastasis

a, TRAMP mice were intercrossed for at least six generations with Ikk ^AA/AA mice. Survival of Ikk ^AA/AA/TRAMP (n = 22) and WT/TRAMP (n = 23) mice was compared. b, c, Histological analysis (haematoxylin and eosin staining of paraffin-embedded sections; magnification, 100) of primary prostate adenocarcinomas from 3-month-old WT/TRAMP (b) and Ikk ^AA/AA/TRAMP (c) mice. d, e, Cell proliferation in prostate carcinomas of 4-month-old WT/TRAMP (c) and Ikk ^AA/AA/TRAMP (d) mice was examined by BrdU labelling. Percentages of BrdU-positive cells are indicated underneath (n = 4). f–j, Incidence of pelvic lymph node (f), renal lymph node (g), liver (h) and lung (i) metastases. j, Average numbers of lymph nodes harbouring metastases (WT/TRAMP, n = 23; Ikk ^AA/AA/TRAMP, n = 22). *P < 0.05; **P < 0.01; error bars, s.d.

原文出处：

Nuclear cytokine-activated IKK controls prostate cancer metastasis by repressing Maspin p690

Jun-Li Luo, Wei Tan, Jill M. Ricono, Olexandr Korchynskyi, Ming Zhang, Steven L. Gonias, David A. Cheresh & Michael Karin

doi:10.1038/nature05656

First paragraph | Full Text | PDF (568K) | Supplementary information

Michael Karin

Affiliation: UCSD SOM

Professor, Department of Pharmacology, School of Medicine

Biography

B.Sc. Biology, 1975, Tel Aviv University, Tel Aviv, Israel
Ph.D. Molecular Biology, 1979, University of California, Los Angeles

Dr. Michael Karin is currently a Professor of Pharmacology at the School of Medicine, University of California, San Diego, where has been on the faculty since 1987. He has served as a member of the Signal Research Division of Celgene since 1992. Dr. Karin also serves as a member of the National Advisory Council for Environmental Health Sciences and has been an American Cancer Society Research Professor since 1999. He is a leading world authority on signal transduction pathways that regulate gene expression in response to extracellular stimuli. Key achievements include definition of cis elements that mediate gene induction by hormones, cytokines and stress, identification and characterization of the transcription factors that recognize these elements and the protein kinase cascades that regulate their activities. Dr. Karin received his Ph.D. in Molecular Biology from UCLA and completed his postdoctoral training at the Fox Chase Institute for Cancer Research (Dr. Beatrice Mintz) and the Departments of Medicine and Biochemistry at the University of California, San Francisco (Dr. John Baxter). He has published over 200 scientific articles and is an inventor on over 14 different patents or pending patent applications. Recently Dr. Karin was ranked first worldwide by the Institute of Scientific Information (ISI) in a recent listing of most-cited molecular biology and genetic research papers published in prestigious journals.

Research Summary

Dr. Karin's research interests focus on five areas of study. 1) Regulation of transcription in mammalian cells by steroid hormones, growth factors, and adverse environmental conditions and during cellular differentiation. Biochemical and genetic approaches are utilized to isolate transacting regulatory proteins, which mediate responses to developmental, hormonal and environmental signals, by binding to specific DNA sequences. Current efforts are to understand the regulation of gene transcription by growth factors, cytokines and polypeptide hormones and cell type specific gene expression. 2) Response of the human genome to stress. The molecular basis for the UV response, the mammalian counterpart of the bacterial SOS response is being studied by various molecular genetics techniques. 3) Protein kinase cascades and their role in growth control, cell differentiation and programmed cell death. These studies focus on the JNK and p38 MAP kinase cascades and their roles in cellular regulation and specific gene induction. 4) The IKK/NF-kB signaling pathway and its physiological and pathophysiological functions. We are most interested in studying IKK and NF-kB as important links between chronic inflammation and cancer. These studies utilize biochemical as well as whole animal approaches. 5) The regulation of mRNA turnover. In addition to gene transcription, an important control point, is mRNA turnover. We are studying both the general mechanisms responsible for rapid mRNA degradation in mammals and the control of protooncogene and cytokine mRNA turnover by extracellular signals.

Dr. Karin made seminal contributions to the discipline of signal transduction describing how extracellular stimuli, including growth factors, cytokines, tumor promoters and UV radiation, regulate gene expression in eukaryotic cells. Starting with cloning of the human metallothionein IIA gene and analysis of its promoter, Karin and coworkers were the first to identify cis elements that mediate induction of cellular genes by stress signals, glucocorticoids and tumor promoters. This resulted in identification of several transcription factors, including AP-1, that recognize these cis elements. AP-1 was subsequently shown by Karin and coworkers to be composed of Jun and Fos proteins. This provided one of the first demonstrations that nuclear protooncoproteins function as transcription factors. Analysis of the mechanisms by which growth factors and UV radiation induce AP-1 activity led to identification of a major signaling pathway (the JNK MAP kinase cascade), elucidation of the mechanisms by which protein phosphorylation controls transcription factor activity and an explanation for the ability of membrane associated oncoproteins, such as Ras, to modulate gene transcription. Karin and coworkers have also described how proinflammatory stimuli regulate the activity of transcription factor NF-kB and identified the IkB kinase (IKK) complex, which they have shown to be a major regulator of innate immunity and inflammation. Genetic analysis of IKK function resulted in identification of a novel signaling pathway that controls development of the mammalian epidermis. Karin and coworkers were also the first to biochemically identify a cell type specific transcription factor (GHF-1/Pit1), demonstrate its kinship to homeodomain proteins and provide important insights to the mechanism of tissue specific gene expression.