Aberrant splicing of the cyclin-dependent kinase-associated phosphatase, KAP, promotes glioblastoma invasion in a Cdc2-dependent manner. However, the mechanism by which this occurs is unknown. Here we show that miR-26a, which is often amplified in glioblastoma, promotes invasion in phosphatase and tensin homolog (PTEN)-competent and PTEN-deficient glioblastoma cells by directly downregulating KAP expression. Mechanistically, we find that KAP binds and activates ROCK2. Thus, RNA-mediated downregulation of KAP leads to decreased ROCK2 activity and this, in turn, increases Rac1-mediated invasion. In addition, the decrease in KAP expression activates the cyclin-dependent kinase, Cdk2, and this directly promotes invasion by increasing retinoblastoma phosphorylation, E2F-dependent Cdc2 expression and Cdc2-mediated inactivation of the actomyosin inhibitor, caldesmon. Importantly, glioblastoma cell invasion mediated by this pathway can be antagonized by Cdk2/Cdc2 inhibitors in vitro and in vivo. Thus, two distinct RNA-based mechanisms activate this novel KAP/ROCK2/Cdk2-dependent invasion pathway in glioblastoma.

2013-06-01·Cancer Letters1区 · 医学

A novel CyclinE/CyclinA-CDK Inhibitor targets p27Kip1 degradation, cell cycle progression and cell survival: Implications in cancer therapy

1区 · 医学

Article

作者: Junyang Liu ; Tao Ye ; Lu Dai ; ZhengShuang Xu ; Shoubin Tang ; Hui Zhang ; Hong Sun ; Yuqing Liu ; Zhuo Wang ; Xiaoming Wen ; Anita R. Maguire ; Junmin Quan

p27(Kip1) (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin-dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1-G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21(Cip1/Waf1) (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival.

2007-12-01·BMC Developmental Biology4区 · 生物学

Wee1 kinase alters cyclin E/Cdk2 and promotes apoptosis during the early embryonic development of Xenopus laevis

4区 · 生物学

ArticleOA

作者: Carla V Finkielstein ; Brian N Wroble ; Jill C Sible

AbstractBackgroundThe cell cycles of the Xenopus laevis embryo undergo extensive remodeling beginning at the midblastula transition (MBT) of early development. Cell divisions 2–12 consist of rapid cleavages without gap phases or cell cycle checkpoints. Some remodeling events depend upon a critical nucleo-cytoplasmic ratio, whereas others rely on a maternal timer controlled by cyclin E/Cdk2 activity. One key event that occurs at the MBT is the degradation of maternal Wee1, a negative regulator of cyclin-dependent kinase (Cdk) activity.ResultsIn order to assess the effect of Wee1 on embryonic cell cycle remodeling, Wee1 mRNA was injected into one-cell stage embryos. Overexpression of Wee1 caused cell cycle delay and tyrosine phosphorylation of Cdks prior to the MBT. Furthermore, overexpression of Wee1 disrupted key developmental events that normally occur at the MBT such as the degradation of Cdc25A, cyclin E, and Wee1. Overexpression of Wee1 also resulted in post-MBT apoptosis, tyrosine phosphorylation of Cdks and persistence of cyclin E/Cdk2 activity. To determine whether Cdk2 was required specifically for the survival of the embryo, the cyclin E/Cdk2 inhibitor, Δ34-Xic1, was injected in embryos and also shown to induce apoptosis.ConclusionTaken together, these data suggest that Wee1 triggers apoptosis through the disruption of the cyclin E/Cdk2 timer. In contrast to Wee1 and Δ34-Xic1, altering Cdks by expression of Chk1 and Chk2 kinases blocks rather than promotes apoptosis and causes premature degradation of Cdc25A. Collectively, these data implicate Cdc25A as a key player in the developmentally regulated program of apoptosis in X. laevis embryos.

项与 CyclinE1/CDK2 inhibitors (Cedilla) 相关的新闻（医药）

2023-06-01

·BioSpace

Bayer to acquire exclusive license from Cedilla Therapeutics on selective inhibitors in pre-clinical precision oncology

Exclusive license agreement includes rights to develop and commercialize Cedilla’s CyclinE1/CDK2 inhibitors Assets are currently in pre-clinical development with potential to serve patients with high unmet need in underserved indications Collaboration further strengthens Bayer’s early pipeline in precision oncology BERLIN & BOSTON--(BUSINESS WIRE)-- Bayer and Cedilla Therapeutics, a biotechnology company bringing a new dimension to precision oncology, today announced an exclusive license agreement to develop and commercialize Cedilla Therapeutics’ CyclinE1/CDK2 complex inhibitors which selectively address oncogenic drivers. Overexpression or genetic activation of Cyclin Dependent Kinase 2 (CDK2) binding partner cyclin E is a key oncogenic process in several cancers. Cedilla’s small molecules conditionally modulate the protein complex in its functional state resulting in highly selective inhibition. This specific method of action that Cedilla has discovered allows for precise targeting in a selected patient population with high unmet need and has the potential to enhance safety and efficacy in comparison to standard of care. “We are excited to bring these highly innovative preclinical programs in-house that complement our early pipeline in precision oncology,” said Dominik Ruettinger, M.D., Ph.D., Global Head of Research and Early Development for Oncology, Pharmaceuticals Division, Bayer AG. “We look forward to progressing Cedilla’s programs and continuing to focus on assets that allow better patient selection. With our oncology strategy, we are dedicated to accelerating the research and development of novel cancer therapies that have the potential to make a meaningful difference in the lives of patients.” “Cedilla is proud to partner with Bayer on this exciting program,” said Neil Exter, Chief Executive Officer of Cedilla Therapeutics and Partner at Third Rock Ventures. “Cedilla's bespoke molecules are designed to inhibit oncogenic drivers, only in their functionally relevant context, thereby unlocking wider therapeutic window and potentially greater efficacy, for targets that are critical and elusive.” Under the terms of the agreement, Bayer will receive full rights on the development and commercialization of Cedilla’s CyclinE1/CDK2 complex inhibitors. Cedilla will receive an upfront payment and potential development and commercial-based milestone payments. Cedilla will also be eligible to receive royalties on medicines based on their technology commercialized by Bayer. Financial details have not been disclosed. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to . Find more information at Follow us on Facebook: Follow us on Twitter: @BayerPharma ime (2023-0113E) Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

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