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来源:本站整理  发布时间:2010/11/10 10:08:20

 主讲人:林慧,2008级硕士研究生,导师:李增山 教授

题目:Diverse somatic mutation patterns and pathway alterations in human cancers.

Nature. 2010 Aug 12;466(7308):869-73. Epub 2010 Jul 28.

Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty
PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K,
Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS,
Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ,
Faham M, Seshagiri S.  

The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics1. Here we report the identification of 2,576 somatic mutations across 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for Ga subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Ga subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.

PubMed PMID: 20668451.

 主讲人: 马晓娟,2008级硕士,导师:王瑞安教授

题目: Akt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis.

Gastroenterology. 2010 Oct;139(4):1397-407. Epub 2010 Jun 20.

Ko FC, Chan LK, Tung EK, Lowe SW, Ng IO, Yam JW.

Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong
Kong, Hong Kong, China.

Comment in:
    Gastroenterology. 2010 Oct;139(4):1093-6.

BACKGROUND & AIMS: Deleted in liver cancer 1 (DLC1), which encodes a Rho GTPase activating protein, is a bona fide tumor suppressor in hepatocellular carcinoma.  Underexpression of DLC1 in cancer has been attributed to genomic deletion and epigenetic silencing. However, the regulatory mechanism of the tumor suppressive activity of DLC1 remains elusive. In this study, we elucidated a novel post-translational modification by which the activity of DLC1 is functionally regulated. METHODS: Molecular and biochemical approaches were employed to study Akt phosphorylation of DLC1. In vitro and in vivo functional assays were performed to elucidate the functional significance of Akt   phosphorylation ofDLC1. RESULTS: Phosphorylation of ectopically expressed and endogenous DLC1 was enhanced upon insulin induction or with Akt expression in liver cancer cell lines. Conversely, addition of a phosphatidylinositol 3-kinase/Akt pathway inhibitor or silencing of Akt attenuated the phosphorylation level of DLC1. Site-directed mutagenesis was employed to replace the serine residue of the consensus Akt substrate motifs of DLC1 with alanine. S567 of DLC1 was identified  as the only target of Akt phosphorylation. S567 is well conserved in all DLC family members. DLC2 was phosphorylated by Akt at the corresponding residue. Functional assays demonstrated that the S567D phosphomimetic DLC1 mutant lost its inhibitory activities in tumorigenesis and metastasis of oncogenically transformed hepatoblasts in a mouse model. CONCLUSIONS: This study has revealed a novel post-translational modification that functionally deregulates the biologic activities of DLC1. Phosphorylation of DLC1 and DLC2 by Akt at the conserved residue points to a common regulatory mechanism of the DLC tumor suppressor family.
PMID: 20600027 [PubMed - indexed for MEDLINE]

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