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Lin, Lin

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Lin, Lin

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2009 - 200912010 - 20162

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Author's Publications: search.filters.isAuthorOfPublication.0b395834-c7f4-4048-accf-0565e91bcd98

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    SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas
    (Springer Nature, 2009) Bass, Adam; Watanabe, Hideo; Mermel, Craig; Yu, Soyoung; Perner, Sven; Verhaak, Roel; Kim, So Jeong; Wardwell, Leslie; Tamayo, Pablo; Gat-Viks, Irit; Ramos, Alex H; Woo, Michele S; Weir, Barbara Ann; Getz, Gad; Beroukhim, Rameen; O, Michael; Dutt, Amit; Rozenblatt-Rosen, Orit; Dziunycz, Piotr; Komisarof, Justin; Chirieac, Lucian; LaFargue, Christopher J; Scheble, Veit; Wilbertz, Theresia; Ma, Changqing; Rao, Shilpa; Nakagawa, Hiroshi; Stairs, Douglas B; Lin, Lin; Giordano, Thomas J; Wagner, Patrick; Minna, John D; Gazdar, Adi F; Zhu, Chang Qi; Brose, Marcia S; Cecconello, Ivan; Jr, Ulysses Ribeiro; Marie, Suely K; Dahl, Olav; Shivdasani, Ramesh; Tsao, Ming-Sound; Rubin, Mark A; Wong, Kwok-Kin; Regev, Aviv; Hahn, William; Beer, David G; Rustgi, Anil K; Meyerson, Matthew
    Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development.1,2 Here we show that a peak of genomic amplification on chromosome 3q26.33, found in squamous cell carcinomas (SCCs) of the lung and esophagus, contains the transcription factor gene SOX2—which is mutated in hereditary human esophageal malformations3 and necessary for normal esophageal squamous development4, promotes differentiation and proliferation of basal tracheal cells5 and co-operates in induction of pluripotent stem cells.6,7,8 SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These observations identify SOX2 as a novel lineage survival oncogene in lung and esophageal SCC.
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    Gastrointestinal Adenocarcinomas of the Esophagus, Stomach, and Colon Exhibit Distinct Patterns of Genome Instability and Oncogenesis
    (American Association for Cancer Research (AACR), 2012) Dulak, A. M.; Schumacher, S. E.; van Lieshout, J.; Imamura, Y.; Fox, Cameron; Shim, B.; Ramos, A. H.; Saksena, G.; Baca, Sylvan; Baselga, J.; Tabernero, J.; Barretina, J.; Enzinger, Peter; Corso, G.; Roviello, F.; Lin, Lin; Bandla, S.; Luketich, J. D.; Pennathur, A.; Meyerson, Matthew; Ogino, Shuji; Shivdasani, Ramesh; Beer, Dennis; Godfrey, T. E.; Beroukhim, Rameen; Bass, Adam
    A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations (SCNAs) in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential utility of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared to colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions.
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    A substrate-driven allosteric switch that enhances PDI catalytic activity
    (Nature Publishing Group, 2016) Bekendam, Roelof H.; Bendapudi, Pavan; Lin, Lin; Nag, Partha P.; Pu, Jun; Kennedy, Daniel R.; Feldenzer, Alexandra; Chiu, Joyce; Cook, Kristina M.; Furie, Bruce; Huang, Mingdong; Hogg, Philip J.; Flaumenhaft, Robert
    Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is a–b–b′–x–a′, wherein the thioredoxin-like a and a′ domains mediate disulfide bond shuffling and b and b′ domains are substrate binding. The b′ and a′ domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of b′. Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation in vivo. Ligation of the substrate-binding pocket by bepristats paradoxically enhances catalytic activity of a and a′ by displacing the x-linker, which acts as an allosteric switch to augment reductase activity in the catalytic domains. This substrate-driven allosteric switch is also activated by peptides and proteins and is present in other thiol isomerases. Our results demonstrate a mechanism whereby binding of a substrate to thiol isomerases enhances catalytic activity of remote domains.