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  • Indeed some cancers may even be

    2020-05-22

    Indeed, some cancers may even be defined by dysregulated cyclin and thus CDK activity: mantle cell lymphoma, an uncommon lymphoma of mature B cells, is defined by the presence of overexpressed cyclin D1, usually as a result of a translocation between chromosomes 11 and 14 with the net result that cyclin D1 is driven under influence of powerful immunoglobulin heavy chain enhancers on chromosome 14. Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western adults [4] and shares many features with mantle cell lymphoma including mature B-cell derivation, B-cell receptor stereotypy, overactive B-cell receptor signaling pathway, and attendant therapeutic vulnerability, but apart from occasional cases it does not share such overexpression of cyclin D [5], [6], [7], [8], [9]. Nevertheless, and although CLL is relatively nonproliferative, ie, noncycling, CDK inhibitors have been studied extensively in CLL and it is in this disease they have shown perhaps the greatest promise. Early studies with alvocidib were limited by hyper acute tumor lysis, a surprising finding in a slowly proliferating tumor treated with an agent putatively acting on cell cycle. Although control and arrest of Plerixafor was an initial motivation for the exploration of CDK inhibitors, other mechanisms were found to be responsible for its powerful antitumor activity in CLL.
    Cyclins control cyclin-dependent kinases In health, the cell cycle is a coordinated balance of internal and external signals that together facilitate quiescent rest or promote orderly and appropriate progression through the various phases of mitotic duplication and division. In a seminal deconstruction of “cancer,” Hanahan and Weinberg proposed that the cancer cell may be defined by—among other things—having gained the ability to progress through mitosis without stimulation by growth factors, or having lost the ability to respond to suppressive signals from within or without; normal cell-cycle checkpoints are bypassed and cancer cells then divide out of control [10]. Cyclins, first discovered in sea urchin eggs [11] in 1983, were the first protein within the eukaryotic cell observed to clearly rise and fall as if by clockwork. This observation and subsequent ones related to cell cycle checkpoint proteins led to the realization that eukaryotic cell cycle both controls and can be controlled by specific protein components and provided the earliest foundations for biochemical understanding of the autonomous cell cycle [1]. In tandem with the discovery of cyclins was that they were a subunit in a larger complex containing also a CDK, the latter of which contributes the catalytic activity. Most cyclins associate with one or two CDKs; similarly, most CDKs pair with one or two cyclins. Table 1 is a brief listing of cyclin partners for various CDKs broken down by phase of cell cycle as well as putative functions, the understanding of which continues to evolve. Although many cyclin–CDK complexes (and possibly CDKs alone) possess non-kinase activity, it is phosphorylation of target proteins by the catalytic CDK that is largely responsible for their cell-cycle regulatory functions [2]. A canonical example is the CDK4–cyclin D complex that promotes the G1–S phase progression (Table 1). While in a hypophosphorylated state, Rb proteins sequester E2F transcription factor family members. CDK4 or CDK6, in conjunction with cyclin D, is capable of phosphorylation of Rb which subsequently frees bound E2F; E2F family transcription factors then bind to DNA to facilitate transcription of target genes responsible for preparation for and entry into S phase under normal conditions, or of oncogenic target genes when dysregulated [3], [12], [13], [14]. Strikingly, and in a beautiful demonstration of the orderly rise-and-fall of individual cyclins, one target that is upregulated by CDK4–cyclin D–mediated E2F activity is cyclin E, which maintains Rb phosphorylation and promotes further passage toward M phase [1].