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发表于 2011-10-19 14:48 |只看该作者 |倒序浏览 |打印

本帖最后由 sunsong7 于 2011-10-19 14:51 编辑
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科学家发现抗癌新基因网络作者：Pier Pandolfi 来源：《细胞》发布时间：2011-10-19 9  ( w1 s7 K+ p% T# t6 l
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哈佛医学院贝丝·伊斯雷尔女执事医疗中心(BIDMC)以及纽约和罗马两个科研团队，发现了存在新的作用巨大的基因网络的证据，并且展示了这些网络推动癌症发展或正常发育的可能方式。这项研究结果对了解癌症及人类健康的遗传学机理具有重要意义。6 D3 H( E4 c" Z" w2 z* C
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《细胞》杂志网络版10月14日发表的四篇论文描述了一种可能是全新的基因活动形式的方方面面，这种活动涉及到大量互相影响并且在幕后摆布分子“残局”的核糖核酸(RNA)分子。每一篇论文都采用了各不相同的方法，从而增加了这一有关新RNA网络的基础性发现的分量。
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这些研究结果可以使研究人员拓宽思路，以便深入探究肿瘤的形成和发展机制，发现癌症高危人群，并寻找和抑制导致癌症生长和扩散的关键的异常分子。

BIDMC癌症遗传学计划负责人皮尔·潘多尔菲博士和哈佛医学院的乔治·赖斯曼教授说：“例如，我们现在知道PTEN肿瘤抑制基因与一个巨大的尚未被认识的RNA网络进行对话。+ g, \5 D, h3 ?3 D8 E
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RNA通过一种新的语言交谈，如果这种语言出了差错，RNA网络受到了破坏，那么PTEN基因就会走下坡路，从而带来毁灭性后果。不过治疗方面的潜力令人极其振奋。你可以改写RNA之间的‘对话’，以便进行癌症的预防和治疗。”赖斯曼是其中两篇论文的主要作者。

《细胞》杂志发表的另一篇相关论文指出，新的RNA管理网络似乎也延伸到了人类基因组中广阔的非蛋白质编码区域，并在正常的肌肉发育过程中发挥着重要作用。由于人类拥有众多与包括蠕虫和酵母在内的其他生物相同的蛋白质编码基因，被转录为非编码RNA的这一广阔区域使得人类的基因组与众不同。这种非编码RNA的功能在很大程度上仍不为人所知。

潘多尔菲说：“几乎所有关于癌症基因的科学分析都把重点放在蛋白质编码基因上。”他指的是把指令从DNA传递至RNA、再传递至蛋白质的那2%的人类基因组。他说：“我们知道，有将近一半被转录成RNA的基因组是不给蛋白质编码的。通过这种新的RNA‘语言’，我们可以把这个空当派上用场。”（来源：新华网）

Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs # F6 k5 g; Z0 e5 ]8 U

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Cell, Volume 147, Issue 2, 344-357, 14 October 2011) c8 V* U* Q4 V& n, o9 X# d2 K" F
Copyright  2011 Elsevier Inc. All rights reserved.
10.1016/j.cell.2011.09.029" U4 }! R/ A$ T
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Authors8 q2 L' A- J, l2 j$ A3 N, }
Yvonne Tay, Lev Kats, Leonardo Salmena, Dror Weiss, Shen Mynn Tan, Ugo Ala, Florian Karreth, Laura Poliseno, Paolo Provero, Ferdinando Di Cunto, Judy Lieberman, Isidore Rigoutsos, Pier Paolo PandolfiSee AffiliationsHint: Rollover Authors and Affiliations Cancer Genetics Program, Division of Genetics, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA1 y7 N8 ^, n3 ^) v8 k, C$ V
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA4 _  T3 H' m+ s# c* Y
Molecular Biotechnology Center and Department of Genetics, Biology, and Biochemistry, University of Turin, Turin, Italy; M! L0 m1 n+ Q; ^% h2 h" r0 V
Computational Medicine Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
Corresponding author" ^  i; s; _! p' C6 v. d8 j
Present address: Department of Dermatology, New York University School of Medicine, 522 First Avenue, Smilow 406, New York, NY 10016, USAHighlights
A microRNA target prediction algorithm predicts candidate PTEN ceRNAs % }( ~' O! p) [/ T* p) d* p
Expression of PTEN ceRNAs significantly correlates with PTEN expression in vivo - G2 f  e# q3 B1 K7 ^+ o: }. L
PTEN ceRNAs modulate PTEN and P-Akt levels in a microRNA-dependent manner
PTEN ceRNAs display tumor-suppressive properties and are lost in human cancer' l% K1 Y8 L7 s+ A  F. a! q0 N  j, [
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Summary
Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs.
http://www.cell.com/abstract/S0092-8674(11)01140-8

A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA

Cell, Volume 147, Issue 2, 358-369, 14 October 2011" p, ]5 h& d% w, A; D" v3 e" t- j2 M- i
Copyright © 2011 Elsevier Inc. All rights reserved.
10.1016/j.cell.2011.09.028
Authors/ X) S: n( F5 J: b, l& p+ n7 e
Marcella Cesana, Davide Cacchiarelli, Ivano Legnini, Tiziana Santini, Olga Sthandier, Mauro Chinappi, Anna Tramontano, Irene BozzoniSee AffiliationsHint: Rollover Authors and Affiliations Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy% Z/ E; @; T* v, a* q5 ]5 \
Department of Physics, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Institut Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Center for Life Nano Science @Sapienza, Istituto Italiano di Tecnologia, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy6 v, g. M4 k \' l4 k
IBPM of Consiglio Nazionale delle Ricerche (CNR), Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Corresponding author6 P4 ], h1 ^9 |4 z4 G" @
These authors contributed equally to the workHighlights
linc-MD1 is a long noncoding cytoplasmic RNA expressed during myoblast differentiation
linc-MD1 acts as a competitive endogenous RNA (ceRNA) for miR-133 and miR-135 targets * l" J$ |& q S* Z, p/ G2 } H
Through these miRNAs, linc-MD1 controls MEF2C and MAML1 and myoblast differentiation & S9 j0 H2 B3 T
linc-MD1 is conserved in humans and levels are reduced in MD1, which governs the time of muscle differentiation by acting as a ceRNA in mouse and human myoblasts. Downregulation or overexpression of linc-MD1 correlate with retardation or anticipation of the muscle differentiation program, respectively. We show that linc-MD1 “sponges” miR-133 and miR-135 to regulate the expression of MAML1 and MEF2C, transcription factors that activate muscle-specific gene expression. Finally, we demonstrate that linc-MD1 exerts the same control over differentiation timing in human myoblasts, and that its levels are strongly reduced in Duchenne muscle cells. We conclude that the ceRNA network plays an important role in muscle differentiation.
http://www.cell.com/abstract/S0092-8674(11)01139-1
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An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma9 F0 r. x; Q8 B

Cell, Volume 147, Issue 2, 370-381, 14 October 2011
Copyright  2011 Elsevier Inc. All rights reserved.
10.1016/j.cell.2011.09.041
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Authors+ \3 N- d4 Q: i( A- b1 ?
Pavel Sumazin, Xuerui Yang, Hua-Sheng Chiu, Wei-Jen Chung, Archana Iyer, David Llobet-Navas, Presha Rajbhandari, Mukesh Bansal, Paolo Guarnieri, Jose Silva, Andrea CalifanoSee AffiliationsHint: Rollover Authors and Affiliations Columbia Initiative in Systems Biology, Columbia University, New York, NY 10032, USA# d9 b5 t8 y0 |0 E8 r4 y) c. N: R
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA( x" t* @+ a0 K' M  t
Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA1 K% N; V2 V/ c+ L8 m; [& m7 G2 |
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA+ M- y; ?6 l4 s) I& M5 j
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Corresponding author0 N3 _/ F- G4 y8 o1 {8 c
These authors contributed equally to this workHighlights. z7 \1 _6 l. w% S! e) S
Computational inference reveals a network of miR-mediated interactions in glioblastoma " w' ]! `  A- U
These interactions regulate thousands of genes, including oncogenes and tumor suppressors * k) A* E# W+ S# O
These interactions regulate miR targets without affecting miR expression " V4 ~3 y  K4 Q8 _  Z/ C
These interactions enable crosstalk between established oncogenic pathways0 X: m( w( i4 e8 g. a

Summary
By analyzing gene expression data in glioblastoma in combination with matched microRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude, comprising more than 248,000 microRNA (miR)-mediated interactions. These include 7,000 genes whose transcripts act as miR sponges and 148 genes that act through alternative, nonsponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype implementation, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. siRNA silencing of 13 miR-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3UTR-dependent manner and to increase tumor cell growth rates. Thus, miR-mediated interactions provide a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus.
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http://www.cell.com/abstract/S0092-8674(11)01152-4 $ Y! x& v6 A, ?4 s  B; A0 h1 Y

In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma

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Cell, Volume 147, Issue 2, 382-395, 14 October 2011
Copyright  2011 Elsevier Inc. All rights reserved.
10.1016/j.cell.2011.09.032/ W/ |: d) K3 J$ W3 u2 }3 v
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Authors# c, u9 W% Z; v0 q, U* X8 c
Florian A. Karreth, Yvonne Tay, Daniele Perna, Ugo Ala, Shen Mynn Tan, Alistair G. Rust, Gina DeNicola, Kaitlyn A. Webster, Dror Weiss, Pedro A. Perez-Mancera, Michael Krauthammer, Ruth Halaban, Paolo Provero, David J. Adams, David A. Tuveson, Pier Paolo PandolfiSee AffiliationsHint: Rollover Authors and Affiliations Cancer Genetics Program, Division of Genetics, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Division of Signal Transduction, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA1 c5 c% E' s2 m! L2 i
Li-Ka Shing Centre, Cambridge Research Institute, CRUK, Robinson Way, Cambridge CB2 0RE, UK( E; f" J  ?5 Y
Molecular Biotechnology Center and Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy/ `" ?4 @3 ~4 y4 Z* k. H% Z
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA( _) M7 I& T2 m3 B  s# z
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1HH, UK* e, Q& u9 p7 d0 y2 Q5 z1 E
Department of Pathology, Yale University, New Haven, CT 06520, USA
Department of Dermatology, Yale University, New Haven, CT 06520, USA
Corresponding authorHighlights7 M( U8 o0 \: P0 K) h1 X, `) P
A Sleeping Beauty screen followed by MuTaME analysis discovered putative PTEN ceRNAs ( p& \* H! C" D# ~% P
The PTEN ceRNA ZEB2 regulates PTEN in a miRNA-independent manner
ZEB2 loss activates PI3K/AKT signaling and promotes cell transformation + d$ J# `6 Q% ~: h' N
Attenuated ZEB2 expression is found in melanoma and other human cancers$ ^4 v7 H2 Q( u4 ?) _# V: S

Summary: d- ^! Q+ w- _& g; J; u1 |
We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis.% n" X3 ~; |( I& l* d3 D
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http://www.cell.com/abstract/S0092-8674(11)01143-3

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