Chlorido(chloro­diphenyl­phosphine-κP)(diphenyl­piperidinophosphine-κP)(η5-penta­methyl­cyclo­penta­dien­yl)ruthenium(II)

The title compound, [Ru(C10H15)Cl(C12H10ClP)(C17H20NP)], is a half-sandwich complex of RuII with the chloro­diphenyl­phosphine ligand formed from the diphenyl­piperidinophosphine and chlorine of the precursor complex [Ru(η5-C5Me5)(κ1P—Ph2PNC5H10)Cl2] by an unexpected reaction with NaBH4. The complex has a three-legged piano-stool geometry, with Ru—P bond lengths of 2.2598 (5) Å for the chloro­phosphine and 2.3303 (5) Å for the amino­phosphine

Oncogene or tumor suppressor : evaluating aurora kinase overexpression in normal cells

The family of Aurora kinases consists of three members (Aurora-A, -B and -C), which have been implicated in the control and regulation of mitotic processes. Erroneous mitosis can lead to chromosomal aberrations and subsequently to aneuploidy. During this process genetic information can be gained or lost, resulting in abnormal levels of regulatory molecules, a major step in carcinogenesis. In multiple types of tumors Aurora kinases have been found overexpressed, highlighting their potential involvement in tumor formation and -progression. These high protein levels have been proposed to be responsible for chromosomal instability and the deactivation of cell cycle checkpoints, which ensure the correct separation and distribution of chromosomes during cell division. Aurora kinases have therefore been regarded as oncogenes. Accordingly, colony formation assays in previous studies show that Aurora-A was effective in transforming rodent cells. In contrast, Aurora-A has recently been reported to be involved in differentiation processes in D. melanogaster and implicated in tumor suppression. This finding foremost raises questions about the role Aurora-A plays in carcinogenesis. This study investigated the effect of Aurora-A and -C overexpression on normal cells. While Aurora-C showed no effect on normal cells, it was discovered that overexpression of Aurora-A caused inhibition of cell growth. This effect was attributed to a growth arrest in G1-phase of the cell cycle. Microarray data suggested that this arrest was triggered by attenuation of Cyclin D1-dependent pathways, as could also be observed by monitoring phosphorylation of the retinoblastoma gene product. Ectopic expression of Cyclin D1 by adenoviral infection was sufficient to overcome the cell cycle arrest in G1. Cyclin D1-mediated rescue of an Aurora-A-induced G1-block did not affect cell proliferation. Instead, cells underwent a second cell cycle arrest in G2/M-phase. Expression of a dominant negative p53 variant allowed progression through mitosis and resulted in incorrect cell division, confirming earlier reports which linked aneuploidization by Aurora-A to a defective p53 pathway. In conclusion it was shown that Aurora-A overexpression can be a factor driving aneuploidization. However, two important pathways need to be deregulated - the Rb-dependent restriction point at the G1/S-transition and the p53 pathway, allowing escape from an Aurora-A induced G2/M-block.Die Familie der Aurora-Kinasen besteht aus drei Mitgliedern (Aurora-A, -B und -C), welche in die Regulation mitotischer Vorgänge involviert sind. Schleichen sich in der Zellteilung Fehler ein, kann es in der Folge zur Aneuploidie kommen. Durch Verlust oder Akkumulation genetischer Information wird die Produktion regulatorischer Proteine beeinträchtigt, was die Krebsentstehung fördern kann. Bei mehreren Krebsarten wurden Aurora-Kinasen in erhöhten Mengen gefunden und mit der Deaktivierung von Zellzykluskontrollpunkten, welche die korrekte Aufteilung der Chromosomen während der Zellteilung überwachen, in Verbindung gebracht. Dies deutet auf ihre mögliche Rolle im Tumorwachstum hin. Aurora-Kinasen werden daher als Onkogene eingestuft. Vorangegangene Studien ergaben, dass Aurora-A die Transformation von Rattenzellen verursacht. Im Gegensatz hierzu wurde berichtet, dass Aurora-A in D. melanogaster für Zelldifferenzierung notwendig ist und als Tumorsuppressor fungieren kann. Das wirft die Frage auf, welche Rolle Aurora-A in der Kanzerogenese tatsächlich spielt. In dieser Arbeit wurde der Einfluss von Aurora-A und -C Überexpression auf normale Zellen untersucht. Während Aurora-C keinen Einfluss hatte, verursachte die Überexpression von Aurora-A eineWachstumshemmung. Grund hierfür ist ein Arrest der Zellen in der G1-Phase des Zellzyklus. mRNA-Expressionsprofile legten nahe, dass der Effekt auf einer Abschwächung von Cyclin D1-abhängigen Signalwegen basierte, wie auch durch die Messung der Phosphorylierung des Retinoblastomaproteins(Rb) bestätigt wurde. Reexpression von Cyclin D1 war ausreichend für die Aufhebung des Zellzyklusarrests in der G1-Phase, doch akkumulierten die Zellen nun in einem zweiten Arrest in der G2/M-Phase. Expression von dominant negativem p53 erlaubte diesen Zellen den zweiten Arrest ebenfalls zu überwinden, was zu Fehlern bei der Zellteilung führte. Diese Beobachtung bestätigte frühere Publikationen, die Aneuploidisierung durch Aurora-A mit einem defekten p53-Signalweg in Verbindung brachten. Zusammenfassend konnte gezeigt werden, dass Überexpression von Aurora-A einen Beitrag zur Aneuploidisierung leisten kann. Dafür ist es jedoch notwendig, dass zwei wesentliche zelluläre Kontrollmechanismen defekt sind - der Rb-abhängige Restriktionspunkt am G1/S-Übergang, sowie der p53-Signalweg, um den Zellzyklusarrest in der G2/M-Phase aufzuheben.submitted by Florian JantscherAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWien, Med. Univ., Diss., 2011OeBB(VLID)171474

Overexpression of Aurora-A in primary cells interferes with S-phase entry by diminishing Cyclin D1 dependent activities

Abstract Background Aurora-A is a bona-fide oncogene whose expression is associated with genomic instability and malignant transformation. In several types of cancer, gene amplification and/or increased protein levels of Aurora-A are a common feature. Results In this report, we describe that inhibition of cell proliferation is the main effect observed after transient overexpression of Aurora-A in primary human cells. In addition to the known cell cycle block at the G2/M transition, Aurora-A overexpressing cells fail to overcome the restriction point at the G1/S transition due to diminished RB phosphorylation caused by reduced Cyclin D1 expression. Consequently, overexpression of Cyclin D1 protein is able to override the Aurora-A mediated G1 block. The Aurora-A mediated cell cycle arrest in G2 is not influenced by Cyclin D1 and as a consequence cells accumulate in G2. Upon deactivation of p53 part of the cells evade this premitotic arrest to become aneuploid. Conclusion Our studies describe that an increase of Aurora-A expression levels on its own has a tumor suppressing function, but in combination with the appropriate altered intracellular setting it might exert its oncogenic potential. The presented data indicate that deactivation of the tumor suppressor RB is one of the requirements for overriding a cell cycle checkpoint triggered by increased Aurora-A levels.</p