生物谷報道：最近一個用小鼠前列腺癌模型所做的實驗研究,，識別出了刺激轉(zhuǎn)移形成的一個信號通道,。當(dāng)一個蛋白配體占據(jù)一個被稱為RANK（receptor activator of nuclear factor κ B）的受體時,，該通道被激發(fā),，并且它還依賴于這種激發(fā)和IKKα (IkB kinase a)的核轉(zhuǎn)位,。一旦進(jìn)入細(xì)胞核中,，被激發(fā)的IKKα就會抑制maspin基因轉(zhuǎn)錄,，該轉(zhuǎn)錄的產(chǎn)物已被明確為前列腺癌和乳腺癌中細(xì)胞遷移和入侵的一個抑制成分,。因此，RANK可能是前列腺癌或乳房腫瘤細(xì)胞中都有的轉(zhuǎn)移行為的一個促進(jìn)劑（啟動子）,。該研究成果被發(fā)表于4月5日出版的《自然》雜志上,。
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.
原文出處：
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
See also: Editor's summary
相關(guān)基因：
TNFRSF11A
Official Symbol: TNFRSF11A and Name: tumor necrosis factor receptor superfamily, member 11a, NFKB activator [Homo sapiens]
Other Aliases: CD265, ODFR, OFE, RANK, TRANCER
Other Designations: osteoclast differentiation factor receptor; receptor activator of nuclear factor-kappa B; tumor necrosis factor receptor superfamily, member 11a; tumor necrosis factor receptor superfamily, member 11a, activator of NFKB
Chromosome: 18; Location: 18q22.1
MIM: 603499
GeneID: 8792
SERPINB5
Official Symbol: SERPINB5 and Name: serpin peptidase inhibitor, clade B (ovalbumin), member 5 [Homo sapiens]
Other Aliases: PI5, maspin
Other Designations: protease inhibitor 5 (maspin); serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 5
Chromosome: 18; Location: 18q21.3
MIM: 154790
GeneID: 5268
CHUK
Official Symbol: CHUK and Name: conserved helix-loop-helix ubiquitous kinase [Homo sapiens]
Other Aliases: IKBKA, IKK-alpha, IKK1, IKKA, NFKBIKA, TCF16
Other Designations: I-kappa-B kinase 1; I-kappa-B kinase-alpha; IKK-a kinase; IkB kinase alpha subunit; Nuclear factor NFkappaB inhibitor kinase alpha; conserved helix-loop ubiquitous kinase
Chromosome: 10; Location: 10q24-q25
MIM: 600664
GeneID: 1147
作者簡介：
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.
References
References From PubMed (NCBI)
