Biological functions of CDK5 and potential CDK5 targeted clinical treatments.

Cyclin dependent kinases are proline-directed serine/threonine protein kinases that are traditionally activated upon association with a regulatory subunit. For most CDKs, activation by a cyclin occurs through association and phosphorylation of the CDK\u27s T-loop. CDK5 is unusual because it is not typically activated upon binding with a cyclin and does not require T-loop phosphorylation for activation, even though it has high amino acid sequence homology with other CDKs. While it was previously thought that CDK5 only interacted with p35 or p39 and their cleaved counterparts, Recent evidence suggests that CDK5 can interact with certain cylins, amongst other proteins, which modulate CDK5 activity levels. This review discusses recent findings of molecular interactions that regulate CDK5 activity and CDK5 associated pathways that are implicated in various diseases. Also covered herein is the growing body of evidence for CDK5 in contributing to the onset and progression of tumorigenesis

Cyclin d1 induces chromosomal instability.

We developed mouse model systems to investigate the potential for cyclin D1 to induce CIN in vivo. In a mammary gland specific Tet-inducible model the acute expression profile regulated by cyclin D1 after 7 days was enriched in genes that rank highly with CIN. We also used a mammary gland targeted model (MMTV) to continuously express cyclin D1. The mice started to develop mammary gland tumors at 400 days and the tumor-free incidence was 40% in MMTV-cyclin D1. The gene expression profile of the tumors showed enrichment for the CIN signature. We next compared cyclin D1 expression and the highest ranking CIN genes to a breast cancer expression database and discovered that expression of genes promoting CIN are highly enriched in luminal subtype and that high cyclin D1 and CIN expression correlate specifically in the luminal B subtype. There is increasing interest in employing drugs in the clinic that exploit CIN in tumors. The high CIN expression index in luminal B breast cancer provides a basis for using Cdk and CIN inhibitors as a targeted therapeutic approach

Kinase independent oncogenic cyclin D1.

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Alternate cyclin D1 mRNA splicing modulates P27\u3csup\u3eKlP1\u3c/sup\u3e binding and cell migration

Cyclin D1 is an important cell cycle regulator but in cancer its overexpression also increases cellular migration mediated by p27KlP1 stabilization and RhoA inhibition. Recently, a common polymorphism at the exon 4-intron 4 boundary of the human cyclin D1 gene within a splice donor region was associated with an altered risk of developing cancer. Altered RNA splicing caused by this polymorphism gives rise to a variant cyclin D1 isoform termed cyclin D1b, which has the same N-terminus as the canonical cyclin D1a isoform but a distinct C-terminus. In this study we show that these different isoforms have unique properties with regard to the cellular migration function of cyclin D1. Whereas they displayed little difference in transcriptional co-repression assays on idealized reporter genes, microarray cDNA expression analysis revealed differential regulation of genes including those that influence cellular migration. Additionally, while cyclin D1a stabilized p27KIP1 and inhibited RhoA-induced ROCK kinase activity, promoting cellular migration, cyclin D1b failed to stabilize p27KIP1 or inhibit ROCK kinase activity and had no effect on migration. Our findings argue that alternate splicing is an important determinant of the function of cyclin D1 in cellular migration

Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes. Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3\u27UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling

Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis.

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis

Cyclin D1 integrates G9a-mediated histone methylation.

Lysine methylation of histones and non-histone substrates by the SET domain containing protein lysine methyltransferase (KMT) G9a/EHMT2 governs transcription contributing to apoptosis, aberrant cell growth, and pluripotency. The positioning of chromosomes within the nuclear three-dimensional space involves interactions between nuclear lamina (NL) and the lamina-associated domains (LAD). Contact of individual LADs with the NL are dependent upon H3K9me2 introduced by G9a. The mechanisms governing the recruitment of G9a to distinct subcellular sites, into chromatin or to LAD, is not known. The cyclin D1 gene product encodes the regulatory subunit of the holoenzyme that phosphorylates pRB and NRF1 thereby governing cell-cycle progression and mitochondrial metabolism. Herein, we show that cyclin D1 enhanced H3K9 dimethylation though direct association with G9a. Endogenous cyclin D1 was required for the recruitment of G9a to target genes in chromatin, for G9a-induced H3K9me2 of histones, and for NL-LAD interaction. The finding that cyclin D1 is required for recruitment of G9a to target genes in chromatin and for H3K9 dimethylation, identifies a novel mechanism coordinating protein methylation

"Not an idle spectator": Geoffrey Hill as model reviewer

Geoffrey Hill’s prose has prompted longstanding critical controversy, much of which turns on the perceived difficulty, intransigence and anachronism of his oeuvre as a whole. This paper proposes that new ways to navigate this controversy can be found in Hill’s preoccupation with the exemplary dimensions of writing – that is, in his interest in the poet’s capacity to offer examples (positive and negative) to a community of readers. The discussion pays particular attention to the connections Hill’s reviews establish between style and ethical choice and between literary difficulty and democracy; connections which are intertwined with his ethics of exemplarity in fundamental ways. The paper also engages with those dimensions of literary exemple-use which emerge in new or unusual ways in his prose: his presentation of ‘models’ or ideals for the organisation of civil society; his treatment of certain literary works as exemplars or embodiments of philosophical ideas; and his procedural tic of ‘sampling’ regularly for the purpose of chastisement the ‘bad example’ set by some of the works he criticises

Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1(-/-) mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1(WT) or cyclin D1(KE) in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1(KE) induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1(WT) and cyclin D1(KE) to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis

Study protocol for screening and diagnosis of fetal alcohol spectrum disorders (FASD) among young people sentenced to detention in Western Australia

Introduction: Prenatal alcohol exposure can cause lifelong disability, including physical, cognitive and behavioural deficits, known as fetal alcohol spectrum disorders (FASD). Among individuals with FASD, engagement with justice services is common. Little is known about the prevalence of FASD among young people engaged with the Australian justice system. This study aims to establish FASD prevalence among sentenced young people in detention in Western Australia (WA), and use the findings to develop a screening tool for use among young people entering detention. Translation of these results will guide the management and support of young people in detention and will have significant implications on the lives of young people with FASD and the future of Australian youth justice services. Methods and analysis: Any sentenced young person in WA aged 10-17...years 11...months is eligible to participate. Young people are assessed for FASD by a multidisciplinary team. Standardised assessment tools refined for the Australian context are used, acknowledging the language and social complexities involved. Australian diagnostic guidelines for FASD will be applied. Information is obtained from young people, responsible adults, teachers and custodial officers. Individualised results and management plans for each young person are communicated to the young person and responsible adult. Prevalence of FASD will be reported and multivariate methods used to identify variables most predictive of FASD and to optimise the predictive value of screening. Ethics and dissemination: Approvals have been granted by the WA Aboriginal Health Ethics Committee, University of WA Human Research Ethics Committee, Department of Corrective Services, and Department for Child Protection and Family Support. Anonymised findings will be disseminated through peer-reviewed manuscripts, presentations and the media. Extensive consultation with stakeholders (including government agencies, detention centre staff, community service providers, the young people and their families or carers) will be ongoing until findings are disseminated and translated