Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are more aggressive in cell cycle abrogation and mammary tumor development. The LMW-E isoforms are tumor specific and accumulate in the cytoplasm due to lack of a nuclear localization sequence (NLS). Therefore, we hypothesized that aberrant localization of LMW-E isoforms leads to molecular events that ultimately contribute to LMW-E breast cancer tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay (RePCA) to identify LMW-E (T1) protein-protein interactions in breast cancer. Using this methodology, we found ATP-citrate lyase (ACLY) as a novel interacting protein of LMW-E (T1) in the cytoplasm. ACLY is a 125kDa homotetrameric enzyme that catalyzes cytoplasmic citrate to acetyl-CoA and oxaloacetate in the de novo lipogenesis pathway. End products of this pathway consist of complex fatty acids that fuel membrane production of highly proliferating cells and lipid-based post-translational modifications that mediate protein-protein interactions. Additionally, we found that LMW-E upregulates ACLY enzymatic activity which leads to lipid droplet formation; thereby providing cells with essential building blocks to support growth. ACLY is also required for LMW-E mediated transformation, migration and invasion in vitro, as well as tumor growth in vivo. Taken together these data suggest a novel interplay between LMW-E and ACLY and how metabolic pathways and the cell cycle are linked in breast cancer tumorigenesis.
","abstract_html":"<p>Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are more aggressive in cell cycle abrogation and mammary tumor development. The LMW-E isoforms are tumor specific and accumulate in the cytoplasm due to lack of a nuclear localization sequence (NLS). Therefore, we hypothesized that aberrant localization of LMW-E isoforms leads to molecular events that ultimately contribute to LMW-E breast cancer tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay (RePCA) to identify LMW-E (T1) protein-protein interactions in breast cancer. Using this methodology, we found ATP-citrate lyase (ACLY) as a novel interacting protein of LMW-E (T1) in the cytoplasm. ACLY is a 125kDa homotetrameric enzyme that catalyzes cytoplasmic citrate to acetyl-CoA and oxaloacetate in the <em>de novo</em> lipogenesis pathway. End products of this pathway consist of complex fatty acids that fuel membrane production of highly proliferating cells and lipid-based post-translational modifications that mediate protein-protein interactions. Additionally, we found that LMW-E upregulates ACLY enzymatic activity which leads to lipid droplet formation; thereby providing cells with essential building blocks to support growth. ACLY is also required for LMW-E mediated transformation, migration and invasion <em>in vitro</em>, as well as tumor growth <em>in vivo</em>. Taken together these data suggest a novel interplay between LMW-E and ACLY and how metabolic pathways and the cell cycle are linked in breast cancer tumorigenesis.</p>","abstract_has_math":false,"creators":["Lucenay, Kim"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Khandan Keyomarsi, Ph.D.","Jill Schumacher, Ph.D.","Wei Zhang, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-05-01T07:00:00Z","date_published":"2015-05-01T07:00:00Z","updated_at":"2026-07-24T05:50:16Z","subjects":["Breast cancer Low molecular weight cyclin E ATP-citrate lyase Retrovirus-based protein complementation assay Lipid droplets","Biology","Cancer Biology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/594","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Khandan Keyomarsi, Ph.D.","Jill Schumacher, Ph.D.","Wei Zhang, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Lucenay, Kim"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2016-05-13T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Breast cancer Low molecular weight cyclin E ATP-citrate lyase Retrovirus-based protein complementation assay Lipid droplets","Biology","Cancer Biology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/594"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are more aggressive in cell cycle abrogation and mammary tumor development. The LMW-E isoforms are tumor specific and accumulate in the cytoplasm due to lack of a nuclear localization sequence (NLS). Therefore, we hypothesized that aberrant localization of LMW-E isoforms leads to molecular events that ultimately contribute to LMW-E breast cancer tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay (RePCA) to identify LMW-E (T1) protein-protein interactions in breast cancer. Using this methodology, we found ATP-citrate lyase (ACLY) as a novel interacting protein of LMW-E (T1) in the cytoplasm. ACLY is a 125kDa homotetrameric enzyme that catalyzes cytoplasmic citrate to acetyl-CoA and oxaloacetate in the de novo lipogenesis pathway. End products of this pathway consist of complex fatty acids that fuel membrane production of highly proliferating cells and lipid-based post-translational modifications that mediate protein-protein interactions. Additionally, we found that LMW-E upregulates ACLY enzymatic activity which leads to lipid droplet formation; thereby providing cells with essential building blocks to support growth. ACLY is also required for LMW-E mediated transformation, migration and invasion in vitro, as well as tumor growth in vivo. Taken together these data suggest a novel interplay between LMW-E and ACLY and how metabolic pathways and the cell cycle are linked in breast cancer tumorigenesis.
"]},{"key":"dc:title","label":"Title","values":["Atp-Citrate Lyase Links Cyclin E to Cellular Metabolism In Breast Cancer"]}]}],"canonical_facts":{"dc:contributor":["Khandan Keyomarsi, Ph.D.","Jill Schumacher, Ph.D.","Wei Zhang, Ph.D."],"dc:creator":["Lucenay, Kim"],"dc:date.available":["2016-05-13T07:00:00Z"],"dc:description.abstract":["Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are more aggressive in cell cycle abrogation and mammary tumor development. The LMW-E isoforms are tumor specific and accumulate in the cytoplasm due to lack of a nuclear localization sequence (NLS). Therefore, we hypothesized that aberrant localization of LMW-E isoforms leads to molecular events that ultimately contribute to LMW-E breast cancer tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay (RePCA) to identify LMW-E (T1) protein-protein interactions in breast cancer. Using this methodology, we found ATP-citrate lyase (ACLY) as a novel interacting protein of LMW-E (T1) in the cytoplasm. ACLY is a 125kDa homotetrameric enzyme that catalyzes cytoplasmic citrate to acetyl-CoA and oxaloacetate in the de novo lipogenesis pathway. End products of this pathway consist of complex fatty acids that fuel membrane production of highly proliferating cells and lipid-based post-translational modifications that mediate protein-protein interactions. Additionally, we found that LMW-E upregulates ACLY enzymatic activity which leads to lipid droplet formation; thereby providing cells with essential building blocks to support growth. ACLY is also required for LMW-E mediated transformation, migration and invasion in vitro, as well as tumor growth in vivo. Taken together these data suggest a novel interplay between LMW-E and ACLY and how metabolic pathways and the cell cycle are linked in breast cancer tumorigenesis.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/594"],"dc:subject":["Breast cancer Low molecular weight cyclin E ATP-citrate lyase Retrovirus-based protein complementation assay Lipid droplets","Biology","Cancer Biology"],"dc:title":["Atp-Citrate Lyase Links Cyclin E to Cellular Metabolism In Breast Cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:16Z"}