Molecular and Cellular Biology / Genetics最新文献

{"title":"Abstract 2432: Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting","authors":"A. Kohut, Antons Martincuks, T. Dellinger, Hua Yu, L. Rodriguez-Rodriguez","doi":"10.1158/1538-7445.AM2021-2432","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2432","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81299832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2393: The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique","authors":"Roslyn M. Ray, L. Lang, S. Pokharel, D. O’Meally, Tristan A. Scott, Chun-Wei Chen, K. Morris","doi":"10.1158/1538-7445.AM2021-2393","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2393","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81649031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2270: Membrane organization of KRas4B with regulatory domain of Raf-1","authors":"Hyunbum Jang, Mingzhen Zhang, R. Nussinov","doi":"10.1158/1538-7445.AM2021-2270","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2270","url":null,"abstract":"A major pathway in RAS-driven cell proliferation is the MAPK (Raf/MEK/ERK) pathway. In cancer, membrane-anchored, proximally located, oncogenic Ras isoforms promote Raf dimerization and fully activate MAPK signaling. Among Ras isoforms, KRas4B is frequently mutated in cancer. In the MAPK pathway, active KRas4B dimer or nanocluster can lead to dimerization of Raf kinase domain enhancing the affinity of the KRas4B-Raf interaction. Recently, we modeled the binary KRas4B-Raf-1 complex and its quaternary assembly with the regulatory domain of Raf-1 containing the Ras binding domain (RBD) and cysteine-rich domain (CRD), and suggested that Raf-1 CRD bolsters the high-affinity interaction of Raf-1 with KRas4B by reducing the KRas4B-RBD fluctuations. For the quaternary assembly, recent in silico studies suggested that KRas4B dimer is aligned through the α3 and α4 helical interface, not the α4 and α5 helical interface due to hindrance to the membrane contact of Raf-1 CRD. The Raf-1 regulatory domain contains the N-terminal region (residues 1-55), RBD, and CRD. However, previous modeling efforts were conducted for the KRas4B-Raf-1 complex in the absence of the N-terminal region. Here, computational studies were performed for the KRas4B-Raf-1 complex with full sequence of Raf-l regulatory domain interacting with monomeric and dimeric KRas4B-GTP at the membrane. Increasing experimental evidences suggested that the N-terminal region of Raf plays a significant role in the Ras interaction and the membrane anchorage of Raf. The membrane interaction of isolated N-terminal segment was investigated as the first step toward the complex model construction. Since oncogenic KRas4B mutants form dimers/nanoclusters at the membrane microdomains that provide the signaling platform for Raf, KRas4B in different mutation states interacting with the membrane microdomains with different lipid composition was also studied. The presence of the N-terminal segment of Raf-1 regulatory domain at the membrane can enhance the stability of KRas4B-Raf-1 and thereby relieving Raf9s autoinhibition toward a kinase domain-accessible state, providing a complete mechanistic picture of the KRas4B-Raf-1 interaction. Our recent work uncovers the mechanism of Raf-1 activation by KRas4B at atomic resolution and highlight how this may help in elucidating vital mechanistic questions in Ras biology. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Hyunbum Jang, Mingzhen Zhang, Ruth Nussinov. Membrane organization of KRas4B with regulatory domain of Raf-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2270.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82067419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB194: Analysis of Hippo/YAP abnormalities in head and neck cancer","authors":"G. Reyes, B. Wuertz, F. Ondrey","doi":"10.1158/1538-7445.AM2021-LB194","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB194","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"11 5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78795566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2473:NR4A1suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation","authors":"Hongshan Guo, Gabriel Golczer, S. Maheswaran, Michael S. Lawrence, D. Haber","doi":"10.1158/1538-7445.AM2021-2473","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2473","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76353733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2135: Functional models of chromosome arm aneuploidies in lung squamous cell carcinoma","authors":"Alison M. Taylor, Sejal Jain, J. Shih, A. Cherniack, R. Beroukhim, M. Meyerson","doi":"10.1158/1538-7445.AM2021-2135","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2135","url":null,"abstract":"Aneuploidy, which we define as whole chromosome or chromosome arm copy number imbalance, is a near-universal characteristic of human cancers. Cancer subtypes are often characterized by tumor specific patterns of chromosome arm copy number alterations; for example, squamous cell carcinomas (SCCs) from different tissues of origin (including lung, head and neck, esophagus, and bladder) have a pattern of chromosome 3p loss and chromosome 3q gain. Although these alterations are frequent, they are not well understood due to difficulty in modeling specific aneuploidy alterations in the matching cell type. However, recent advances in genome engineering allow generation of large chromosomal alterations. We used the CRISPR-Cas9 system to delete one copy of chromosome 3p in human immortalized lung epithelial cells most similar to upper airway basal cells. Deletion of chromosome 3p was validated by whole genome sequencing and karyotyping. Consistent with patient data, expression of 3p genes was decreased upon deletion, as well as increased expression of interferon response genes. Phenotypic characterization revealed that cells with chromosome 3p deletion initially proliferated more slowly than their siblings. These chromosome 3p deleted cells had increased G1 arrest but did not undergo increased apoptosis or cell death. Interestingly, after several passages in culture, the proliferation defect was rescued in chromosome 3p deleted cells. Genome sequencing and karyotype analyses found that evidence of chromosome 3 duplication, transitioning the cell to a state of chromosome 3q gain. We isolated sibling cells with chromosome 3p deletion or chromosome 3q gain and demonstrated that duplication of chromosome 3 could indeed rescue proliferation rates. With our cellular model of chromosome arm-level aneuploidy, we uncovered a selection mechanism that allowed aneuploidy tolerance in vitro, and a possible explanation for joint alteration of both arms of chromosome 3. In conclusion, our genome engineering approach to model chromosome arm-level deletions provides a robust model that will address a gap in our understanding of aneuploidy in cancer. Citation Format: Alison Marie Taylor, Sejal Jain, Juliann Shih, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson. Functional models of chromosome arm aneuploidies in lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2135.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76517468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2376: Diagnostic and predictive biomarkers of radiation pneumonitis","authors":"Marshleen Yadav, Joseph Liu, Zahida Qamri, Naduparambil K. Jacob","doi":"10.1158/1538-7445.AM2021-2376","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2376","url":null,"abstract":"Increased rates of treatment failure in lung cancer patients necessitate treatment with high doses of radiation, which often cause toxicities. However, normal tissue injury in lung may manifest as acute toxicities or as delayed radiation pneumonitis. Identification of early indicators of delayed toxicities will allow timely management and mitigation. In present study, using mouse model, we identified a set of circulating microRNAs as biomarkers that potentially allow early detection of radiation induced lung injury such as inflammation and pneumonitis. Longitudinal analysis of serum samples collected from mice exposed to whole thorax lung irradiation (WTLI) allowed discovery of a panel of evolutionary conserved miRNAs that are potential predictors of radiation pneumonitis. Among these, miR21 and miR29a, miR130a, and miR19a were found peaked between 2-4 weeks after radiation, while miR146a exhibited a peculiar biphasic expression. Some of these changes were found to be associated with concomitant changes in anti- and pro-inflammatory serum cytokines. Several of the biomarkers identified in WTLI model, showed overlapping response in a bleomycin mouse model of acute lung injury. We further tested the translational utility of these biomarkers in single drop blood collected from mice using a validated internal normalizer, miR23a (Yadav et al., Science Translational Medicine, 2020, PMID: 32669422). The response noted for several of the candidate biomarkers identified in mouse model are conserved in specimens collected from human patients who received radiation therapy. In conclusion, our study has identified a panel of microRNA biomarkers with potential to develop as early predictor of pulmonary toxicities in patients receiving therapeutic radiation, and in victims of radiation accidents for timely mitigation. Citation Format: Marshleen Yadav, Joseph Liu, Zahida Qamri, Naduparambil K. Jacob. Diagnostic and predictive biomarkers of radiation pneumonitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2376.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"313 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76546068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2081: Transcriptional silencing of CDK18 in BRG1 mutant lung cancer","authors":"Loryn M Phillips, C. A. Johnston, S. Belinsky, M. Tessema","doi":"10.1158/1538-7445.AM2021-2081","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2081","url":null,"abstract":"In ~10% of lung cancers, the BRG1 gene is mutated often causing a loss of function (LOF). BRG1 is a tumor suppressor that encodes a protein (SMARCA4), which is one of the mutually exclusive ATPase subunits of the Switch/Sucrose Non-fermentable (SWI/SNF) complex. The SWI/SNF complex functions to regulate transcription of many genes including tumor suppressor genes, through mediating chromatin remodeling and nucleosome repositioning by maintaining open chromatin and actively evicting polycomb repressive complexes (PRCs) from target genes and regions. Our previous research showed that BRG1 mutation occurs in approximately 9% of lung adenocarcinomas in smokers and 11% in smokers delineating BRG1 as a clinically relevant mutation. The goal of these studies is to elucidate the downstream effects of BRG1 LOF on gene expression. RNA sequencing of isogenic BRG1 wild type (WT) and knock out (KO) clones from malignant and transformed cell lines identified cell cycle control and chromosomal replication as the most significantly affected pathway. qRT-PCR was used to validate expression changes in 17 genes from this pathway in the WT and KO clones as well as wild type and mutant tumors lines. CDK18 was the most significantly affected target exhibiting a 78% reduction in expression (p Citation Format: Loryn Michelle Phillips, Christopher A. Johnston, Steven A. Belinsky, Mathewos Tessema. Transcriptional silencing of CDK18 in BRG1 mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2081.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86869486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2299: An unbiased in vivo screen for activating EGFR mutations","authors":"D. Chakroborty, K. Kurppa, K. Elenius","doi":"10.1158/1538-7445.AM2021-2299","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2299","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87108862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2156: Genomics and molecular analysis of Aurora kinase B (AURKB) in response to antiretroviral (ARV) treatment in lung cancer","authors":"R. Marima, Rodney Hull, Zodwa Dlamini, C. Penny","doi":"10.1158/1538-7445.AM2021-2156","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2156","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87478591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}