Loss of Cdk2 and Cyclin A2 Impairs Cell Proliferation and Tumorigenesis

Gopinathan, Lakshmi; Tan, Shawn Lu Wen; Padmakumar, V. C.; Coppola, Vincenzo; Tessarollo, Lino; Kaldis, Philipp

doi:10.1158/0008-5472.can-13-3440

Cited by 106 publications

(77 citation statements)

References 34 publications

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“…Our observations of the functional connection between USP7/PHF8 and cyclin A2 agree with recent studies reporting that PHF8 promotes cell cycle transition (9,56). In addition, data from the Human Protein Atlas and the literature indicate that cyclin A2 is overexpressed in dozens of cancers (38,39,57), and inhibition of cyclin A2 complexes was shown to suppress tumorigenesis in vitro and in vivo (39,58). Consistent with our observation that USP7-promoted PHF8 stabilization is linked to upregulation of cyclin A2, we showed that the expression level of cyclin A2 is elevated and positively associated with that of PHF8 and USP7 in clinical breast cancer samples.…”

Section: Discussionsupporting

confidence: 91%

“…Deregulation of cyclin A2 was associated with erroneous cell proliferation and chromosomal instability (38,39), and aberrant expression of cyclin A2 has been linked to multiple types of malignancies, including breast, liver, and lung cancers (38)(39)(40). In light of our observation that USP7-mediated deubiquitination and stabilization of PHF8 regulate the expression of cyclin A2, it is reasonable to postulate that the USP7/PHF8 signaling pathway plays a role in cell proliferation and carcinogenesis.…”

Section: Resultsmentioning

confidence: 88%

See 1 more Smart Citation

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

Wang¹,

Ma²,

Song³

et al. 2016

Journal of Clinical Investigation

167

172

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 88%

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

Wang¹,

Ma²,

Song³

et al. 2016

Journal of Clinical Investigation

167

172

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“…In mouse embryos, cyclin B1 is essential to bring cells into mitosis . Cyclin A2, the somatic paralogue of the mammalian cyclin A family, is essential for development, but mouse embryonic fibroblasts can proliferate in the absence of this cyclin . In mammalian cells, cyclin A2 depletion causes defects both in S‐phase progression and in G2 phase .…”

Section: Pulling the Trigger: Cdk1 Activationmentioning

confidence: 99%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

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“…Mice with loss of Ccna2 exhibit early embryonic lethality (48). In cancer, Ccna2 is often aberrantly expressed and impacts cell proliferation (49). The CDC25 protein phosphatases (CDC25A, -B, and -C) drive cell cycle transitions by activating key components of the cell cycle engine (50).…”

Section: Discussionmentioning

confidence: 99%

WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets

Suzuki

Pelikan

Iwata

2015

Molecular and Cellular Biology

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cMolecules involved in WNT/␤-catenin signaling show specific spatiotemporal expression and play vital roles in myogenesis; however, it is still largely unknown how WNT/␤-catenin signaling regulates each step of myogenesis. Here, we show that WNT/ ␤-catenin signaling can control diverse biological processes of myogenesis by regulating step-specific molecules. In order to identify the temporally specific roles of WNT/␤-catenin signaling molecules in muscle development and homeostasis, we used in vitro culture systems for both primary mouse myoblasts and C2C12 cells, which can differentiate into myofibers. We found that a blockade of WNT/␤-catenin signaling in the proliferating cells decreases proliferation activity, but does not induce cell death, through the regulation of genes cyclin A2 (Ccna2) and cell division cycle 25C (Cdc25c). During muscle differentiation, the inhibition of WNT/␤-catenin signaling blocks myoblast fusion through the inhibition of the Fermitin family homolog 2 (Fermt2) gene. Blocking WNT/␤-catenin signaling in the well-differentiated myofibers results in the failure of maintenance of their structure by disruption of cadherin/␤-catenin/actin complex formation, which plays a crucial role in connecting a myofiber's cytoskeleton to the surrounding extracellular matrix. Thus, our results indicate that WNT/␤-catenin signaling can regulate multiple steps of myogenesis, including cell proliferation, myoblast fusion, and homeostasis, by targeting step-specific molecules.S keletal muscle plays highly specialized roles in the generation of force and is capable of extensive metabolic and functional plasticity. Skeletal muscle also exhibits robust regenerative capacity, and its formation is composed of complex and highly regulated processes among embryonic development and regeneration in mature skeletal musculature (1). Muscle precursor cells (also known as satellite cells in the adult) lie under, or are embedded in, the basal lamina of the myofiber in skeletal muscles and are the major source of regeneration and growth of skeletal muscles (2). During development and regeneration in response to injury or recovery from atrophy, muscle precursor cells start to proliferate, at which stage they are referred to as myoblasts, and subsequently differentiate to form new myofibers or fuse with existing myofibers (2). These processes require fine-tuned regulations of proliferation and differentiation that are likely regulated by signal transduction pathways.The WNT family (wingless-type mouse mammary tumor virus [MMTV] integration site family) of signaling molecules consists of 21 secreted glycoprotein ligands. WNT ligands are essential to activate downstream pathways (canonical ␤-catenin-dependent and/or noncanonical ␤-catenin-independent pathways) in physiological and pathological conditions. WNT/␤-catenin signaling can regulate a variety of genes in a specific spatiotemporal manner (3). In the absence of WNT ligands, ␤-catenin is incorporated into a protein complex containing axin, adenomatous polyposis coli (A...

show abstract

Loss of Cdk2 and Cyclin A2 Impairs Cell Proliferation and Tumorigenesis

Cited by 106 publications

References 34 publications

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

Triggering mitosis

WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets

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