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ATP-citrate lyase links cyclin E to cellular metabolism in breast cancer

Kim Lucenay-2015-01-01-Digital Commons-TMC (Texas Medical Center)

TL;DRAbstract

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 co

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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 co

Keywords

ATP citrate lyaseMetabolismBreast cancerBiochemistryChemistryCellular metabolismCell biologyCitrate synthase

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