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18 results on '"Gnanapradeepan, Keerthana"'

2. Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma

Author

Webster, Marie R., Fane, Mitchell E., Alicea, Gretchen M., Basu, Subhasree, Kossenkov, Andrew V., Marino, Gloria E., Douglass, Stephen M., Kaur, Amanpreet, Ecker, Brett L., Gnanapradeepan, Keerthana, Ndoye, Abibatou, Kugel, Curtis, Valiga, Alexander, Palmer, Jessica, Liu, Qin, Xu, Xiaowei, Morris, Jessicamarie, Yin, Xiangfan, Wu, Hong, Xu, Wei, Zheng, Cathy, Karakousis, Giorgos C., Amaravadi, Ravi K., Mitchell, Tara C., Almeida, Filipe V., Xiao, Min, Rebecca, Vito W., Wang, Ying-Jie, Schuchter, Lynn M., Herlyn, Meenhard, Murphy, Maureen E., and Weeraratna, Ashani T.

Published
2020
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5. Supp Materials and Methods from A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors

Author

Barnoud, Thibaut, primary, Leung, Jessica C., primary, Leu, Julia I-Ju, primary, Basu, Subhasree, primary, Poli, Adi Narayana Reddy, primary, Parris, Joshua L.D., primary, Indeglia, Alexandra, primary, Martynyuk, Tetyana, primary, Good, Madeline, primary, Gnanapradeepan, Keerthana, primary, Sanseviero, Emilio, primary, Moeller, Rebecca, primary, Tang, Hsin-Yao, primary, Cassel, Joel, primary, Kossenkov, Andrew V., primary, Liu, Qin, primary, Speicher, David W., primary, Gabrilovich, Dmitry I., primary, Salvino, Joseph M., primary, George, Donna L., primary, and Murphy, Maureen E., primary

Published
2023
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6. Supplemental Figures from A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors

Author

Barnoud, Thibaut, primary, Leung, Jessica C., primary, Leu, Julia I-Ju, primary, Basu, Subhasree, primary, Poli, Adi Narayana Reddy, primary, Parris, Joshua L.D., primary, Indeglia, Alexandra, primary, Martynyuk, Tetyana, primary, Good, Madeline, primary, Gnanapradeepan, Keerthana, primary, Sanseviero, Emilio, primary, Moeller, Rebecca, primary, Tang, Hsin-Yao, primary, Cassel, Joel, primary, Kossenkov, Andrew V., primary, Liu, Qin, primary, Speicher, David W., primary, Gabrilovich, Dmitry I., primary, Salvino, Joseph M., primary, George, Donna L., primary, and Murphy, Maureen E., primary

Published
2023
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7. Elucidating the Role of the African-Centric P47s Variant of TP53 in Metabolism and Ferroptosis

Author

Gnanapradeepan, Keerthana and Gnanapradeepan, Keerthana

Abstract

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer and plays a key role in mediating several processes that are critical for preventing tumor formation and progression. Known as the guardian of the genome, p53 regulates hundreds of genes involved in various pathways such as apoptosis, cell cycle arrest and senescence. In recent years, the role of p53 in metabolism, redox state and ferroptosis has begun to emerge. Our lab has identified an African-specific polymorphic variant of p53 that encodes a serine residue instead of a proline at amino acid 47 (hereafter S47) and predisposes carriers to cancer. The S47 variant is impaired for tumor suppression and ferroptosis, and S47 cells have an altered redox state. We sought to use the tumor prone S47 model as a tool to better understand the role of p53 in tumor suppression. Our results demonstrate that mice carrying the S47 variant have greater metabolic efficiency compared to those with WT p53, along with increased mTOR activity. This difference in mTOR stems from an impaired protein-protein interaction that occurs in S47, ultimately due to a difference in cellular redox state. We next identified PLTP as a p53 target gene that shows decreased transactivation in the S47 variant and mediates ferroptosis resistance by enhancing lipid storage in HepG2 cells. Taken together, this work sheds light on the emerging roles p53 plays in tumor suppression, metabolism and ferroptosis. It also provides a better understanding of an ethnic genetic variant of p53. We expect this work will enable better personalized medicine approaches and therapeutic options for people who carry this variant.

Published
2021

8. A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors

Author

Barnoud, Thibaut, primary, Leung, Jessica C., additional, Leu, Julia I-Ju, additional, Basu, Subhasree, additional, Poli, Adi Narayana Reddy, additional, Parris, Joshua L.D., additional, Indeglia, Alexandra, additional, Martynyuk, Tetyana, additional, Good, Madeline, additional, Gnanapradeepan, Keerthana, additional, Sanseviero, Emilio, additional, Moeller, Rebecca, additional, Tang, Hsin-Yao, additional, Cassel, Joel, additional, Kossenkov, Andrew V., additional, Liu, Qin, additional, Speicher, David W., additional, Gabrilovich, Dmitry I., additional, Salvino, Joseph M., additional, George, Donna L., additional, and Murphy, Maureen E., additional

Published
2020
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10. Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser

Author

Gnanapradeepan, Keerthana, primary, Leu, Julia I-Ju, additional, Basu, Subhasree, additional, Barnoud, Thibaut, additional, Good, Madeline, additional, Lee, Joyce V, additional, Quinn, William J, additional, Kung, Che-Pei, additional, Ahima, Rexford, additional, Baur, Joseph A, additional, Wellen, Kathryn E, additional, Liu, Qin, additional, Schug, Zachary T, additional, George, Donna L, additional, and Murphy, Maureen E, additional

Published
2020
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11. Author response: Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser

Author

Gnanapradeepan, Keerthana, primary, Leu, Julia I-Ju, additional, Basu, Subhasree, additional, Barnoud, Thibaut, additional, Good, Madeline, additional, Lee, Joyce V, additional, Quinn, William J, additional, Kung, Che-Pei, additional, Ahima, Rexford, additional, Baur, Joseph A, additional, Wellen, Kathryn E, additional, Liu, Qin, additional, Schug, Zachary T, additional, George, Donna L, additional, and Murphy, Maureen E, additional

Published
2020
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12. Abstract 3483: The African-specific S47 variant of the p53 tumor suppressor gene alters cell metabolism

Author

Gnanapradeepan, Keerthana, primary, Basu, Subhasree, additional, Kung, Che-Pei, additional, Barnoud, Thibaut, additional, Good, Madeline, additional, Quinn, William, additional, Lee, Joyce, additional, Wellen, Kathryn, additional, Schug, Zachary, additional, Baur, Joseph, additional, George, Donna, additional, and Murphy, Maureen, additional

Published
2019
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14. Prospective functional classification of all possible missense variants in PPARG

Author

Majithia, Amit R, Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert, Peloso, Gina, Patel, Kashyap A, Zhang, Xiaolan, Broekema, Marjoleine F, Patterson, Nick, Duby, Marc, Sharpe, Ted, Kalkhoven, Eric, Rosen, Evan D, Barroso, Inês, Ellard, Sian, UK Monogenic Diabetes Consortium, Kathiresan, Sekar, Myocardial Infarction Genetics Consortium, O'Rahilly, Stephen, UK Congenital Lipodystrophy Consortium, Chatterjee, Krishna, Florez, Jose C, Mikkelsen, Tarjei, Savage, David B, Altshuler, David, Barroso, Ines [0000-0001-5800-4520], O'Rahilly, Stephen [0000-0003-2199-4449], Chatterjee, Krishna [0000-0002-2654-8854], Savage, David [0000-0002-7857-7032], and Apollo - University of Cambridge Repository

Subjects
Male, PPAR gamma, Amino Acid Substitution, Diabetes Mellitus, Type 2, Lipodystrophy, Case-Control Studies, Macrophages, Mutation, Missense, Myocardial Infarction, Humans, Female, Prospective Studies
Abstract

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.

Published
2016

17. Prospective functional classification of all possible missense variants in PPARG

Author

Majithia, Amit R., Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert, Peloso, Gina, Patel, Kashyap A., Zhang, Xiaolan, Broekema, Marjoleine F., Patterson, Nick, Duby, Marc, Sharpe, Ted, Kalkhoven, Eric, Rosen, Evan D., Barroso, Inês, Ellard, Sian, Kathiresan, Sekar, O’Rahilly, Stephen, Chatterjee, Krishna, Florez, Jose C., Mikkelsen, Tarjei, Savage, David B., and Altshuler, David

Abstract

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty1,2. For example, mutations in PPARG cause Mendelian lipodystrophy3,4 and increase risk of type 2 diabetes (T2D)5. While approximately one in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning (http://miter.broadinstitute.org). When applied to 55 novel missense variants identified in population-based and clinical sequencing, the classifier annotated six as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.

Published
2016
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18. Prospective functional classification of all possible missense variants in PPARG

Author

Majithia, Amit R, Tsuda, Ben, Agostini, Maura, Gnanapradeepan, Keerthana, Rice, Robert, Peloso, Gina, Patel, Kashyap A, Zhang, Xiaolan, Broekema, Marjoleine F, Patterson, Nick, Duby, Marc, Sharpe, Ted, Kalkhoven, Eric, Rosen, Evan D, Barroso, Inês, Ellard, Sian, UK Monogenic Diabetes Consortium, Kathiresan, Sekar, Myocardial Infarction Genetics Consortium, O'Rahilly, Stephen, UK Congenital Lipodystrophy Consortium, Chatterjee, Krishna, Florez, Jose C, Mikkelsen, Tarjei, Savage, David B, and Altshuler, David

Subjects
Male, PPAR gamma, Amino Acid Substitution, Diabetes Mellitus, Type 2, Lipodystrophy, Case-Control Studies, Macrophages, Mutation, Missense, Myocardial Infarction, Humans, Female, Prospective Studies, 3. Good health
Abstract

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.

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