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The G1 cell-cycle kinase CDK6 has long been thought of as a redundant homolog of CDK4. Although the two kinases have very similar roles in cell-cycle progression, it has recently become apparent that they differ in tissue-specific functions and contribute differently to tumor development. CDK6 is directly involved in transcription in tumor cells and in hematopoietic stem cells. These functions point to a role of CDK6 in tissue homeostasis and differentiation that is partially independent of CDK6's kinase activity and is not shared with CDK4. We review the literature on the contribution of CDK6 to transcription in an attempt to link the new findings on CDK6's transcriptional activity to cell-cycle progression. Finally, we note that anticancer therapies based on the inhibition of CDK6 kinase activity fail to take into account its kinase-independent role in tumor development.

IntroductionUrbanization is a global phenomenon that is encroaching on natural habitats and decreasing biodiversity, although it is creating new habitats for some species. The Eurasian kestrel (Falco tinnunculus) is frequently associated with urbanized landscapes but it is unclear what lies behind the high densities of kestrels in the urban environment.ResultsOccupied nest sites in the city of Vienna, Austria were investigated along a gradient of urbanization (percentage of land covered by buildings or used by traffic). Field surveys determined the abundance of potential prey (birds and rodents) and the results were compared to the birds’ diets. A number of breeding parameters were recorded over the course of three years. The majority of kestrels breed in semi-natural cavities in historic buildings. Nearest neighbour distances (NND) were smallest and reproductive success lowest in the city centre. Abundance of potential prey was not found to relate to the degree of urbanization but there was a significant shift in the birds’ diets from a heavy reliance on rodents in the outskirts of the city to feeding more on small birds in the centre. The use of urban habitats was associated with higher nest failure, partly associated with predation and nest desertion, and with significantly lower hatching rates and smaller fledged broods.ConclusionsHigh breeding densities in urban habitats do not necessarily correlate with high habitat quality. The high density of kestrel nests in the city centre is probably due to the ready availability of breeding cavities. Highly urbanized areas in Vienna are associated with unexpected costs for the city dwelling-raptor, in terms both of prey availability and of reproductive success. The kestrel appears to be exploiting the urban environment but given the poor reproductive performance of urban kestrels it is likely that the species is falling into an ecological trap.

In eukaryotes the transcriptional control of RNA polymerase II-mediated gene expression is exerted by cis-acting regulatory DNA elements classified as promoter and enhancer sequences. These elements are composed of a number of different protein binding sites. The regulatory factors that recognize such 'modules' may be ubiquitous, tissue- or stage-specific, and positively or negatively acting. According to this model the transcriptional activity of a given gene is programmed by a combination of different modules. We analysed such a site of protein-DNA interaction, the octamer motif, in the enhancers of the simian virus (SV40) early genes and the murine immunoglobulin heavy-chain gene, and in the distal sequence element (DSE) of the U2 small nuclear (sn)RNA gene of Xenopus laevis. The corresponding DNA-binding factor appears to be the same in the three cases. Moreover, a fraction containing partially purified octamer motif binding factor has a stimulatory effect on transcription in an in vitro system.

HomothaUic haploid yeast cells divide to produce a mother cell that switches mating type and a daughter cell that does not. This pattern is the result of HO endonuclease transcription exclusively in mother cells, and there only transiently in late G1 as cells undergo Start. SWI5 encodes an HO transcription factor that is expressed during the S, G2, and M phases of the cell cycle. The lack of synthesis of SWI5 during G1 is essential to prevent HO transcription in daughter cells. Thus, HO must be activated by SWI5 protein synthesized in the previous cell cycle if it is to be properly regulated. SWI5 is inherited by both mother and daughter cells, and we show here that most of it is rapidly degraded during early G1. More stable mutant SWI5 proteins cause daughter cells to switch mating type, suggesting that SWI5 destruction is necessary to prevent HO expression in daughters. We show further that mother cells can still express HO when stimulated to undergo Start after arrest in early G1 for several hours. We propose that a small fraction of the SWI5 protein inherited by mother cells is extremely stable and that the crucial difference between mothers and daughters with regard to HO transcription is their differential ability to sequester SWI5 in a stable form, possibly as a component of transcription complexes on the HO promoter.

The yeast HO gene is transcribed transiently during G~ as cells undergo START. START-specific HO activation requires two proteins, SWI4 and SWI6, which act via a motif (CACGA4) repeated up to 10 times within the URS2 region of the HO promoter. We identified a DNA-binding activity containing SWI4 and SWI6 that recognizes the CACGA 4 sequences within URS2. Two forms of SWI4,6-DNA complexes called L and U can be distinguished by their electrophoretic mobility. L complexes can be detected at all stages of the cell cycle, but U complexes are only detected in cells that have undergone START. The formation of U complexes may be the trigger of HO activation. The SWI6 protein is concentrated in the nucleus throughout G1, but at some point in S or G 2 significant amounts accumulate in the cytoplasm. This change in cellular location of the SWI6 protein might contribute to the turnoff of HO trancription after cells have undergone START.

The proximal sequence element (PSE) of a Xenopus U2 snRNA gene has been analysed by extensive local mutagenesis. The PSE is compact, lying between -61 and -50 bp upstream of the transcription start site and is involved in signalling both transcription initiation and 3' end formation. No PSE mutants were found in which these two activities were differentially affected. Analysis of U2 gene promoters mutant in both the PSE and DSE failed to reveal any evidence for multiple signals involved in 3' end formation, leading to the conclusion that the PSE is the only promoter element required for this function. The U2 and U6 PSEs, which direct either pol II or both pol II and pol III transcription respectively, are shown to be functionally interchangeable. Apparent differences in human and Xenopus U2 gene PSE structure are discussed.