In this issue

The general transcription factor (GTF) TFIID comprises the TATA-box-binding protein (TBP) and a group of transcriptional coactivators termed TBP-associated factors (TAF_IIs). One of these coactivators,TAF_II250, possesses a variety of enzymatic activities and seems to play a central role in control of RNA-polymerase-II-dependent transcription. David Wassarman and Frank Sauer discuss recent work that has shed light on the functions of TAF_II250. The protein appears to bind to core promoter elements and act as a scaffold for assembly of TAF_IIs and TBP into TFIID. Furthermore, it can bind to transcriptional regulators such as JUN and pRB and thereby recruit TFIID to particular promoters. TAF_II250 possesses protein kinase, ubiquitin-activating/conjugating and acetylase activities, which can modify histones and GTFs. Wassarman and Sauer propose that this `tool box' of enzymatic activities allows TAF_II250 to position/stabilize TFIID at promoters and alter local chromatin structure to facilitate assembly of GTFs in pre-initiation complexes.

Activation of PI 3-kinases is a feature of many signalling pathways that respond to extracellular stimuli and plays a central role in regulation of cell cycle progression and apoptosis. Recent work indicates that the D3-phosphorylated lipid products of PI 3-kinase activate the Ser/Thr kinase protein kinase B (PKB/Akt), which could therefore be an important downstream effector in PI 3-kinase signalling. Margaret Lawlor and Dario Alessi review studies that suggest PKB plays key roles in insulin signalling and cancer progression, discussing these findings in the context of predicted PKB substrates. PKB has been shown to be essential for normal glucose homeostasis,and relevant PKB targets in insulin signalling include glycogen synthase kinase 3 (GSK3) and insulin receptor substrate 1 (IRS1). During cancer progression, PKB promotes cell proliferation and inhibits apoptosis of tumour cells - in this case, phosphorylating proteins such as the cell cycle inhibitor p21 and the apoptosis mediator BAD. Given the importance of PKB in these processes, Lawlor and Alessi discuss its potential as a therapeutic target for treatment of cancer and diabetes.

Accurate segregation of chromosomes is essential during both mitosis and meiosis. Errors at meiosis, for example, can lead to gamete loss, reduced fertility and aneuploidy such as that evident in Down syndrome. The checkpoints that ensure that chromosomes segregate correctly at mitosis are relatively well understood, but we know much less about meiotic checkpoints. To gain further insight into meiotic checkpoints, Mary Ann Handel and co-workers have analysed sperm from male mice that possess Robertsonian (Rb)chromosomes - metacentric or nearly metacentric chromosomes produced by fusion of two acrocentric chromosomes. They show that, despite abnormalities in chromosome pairing and alignment on the spindle, the prophase-metaphase transition occurs normally in heterozygous Rb mice spermatocytes. However,there is increased apoptosis during metaphase I, particularly in spermatocytes that contain misaligned chromosomes. The authors also show that the kinetochores of misaligned chromosomes stain intensely for CENP-E and CENP-F -proteins associated with mitotic spindle-assembly checkpoints. Their data suggest that spermatocytes possess a meiotic spindle-assembly checkpoint that monitors attachment/congression of homologous chromosome pairs and induces apoptosis if errors have occurred.

Polyploidy - the accumulation of large amounts of DNA through DNA synthesis in the absence of cell division - occurs in lower and higher eukaryotes. It is common in terminally differentiated and senescent mammalian cells; however,the biological significance of the phenomenon and its regulation are unclear. Sanjeev Gupta and co-workers have investigated polyploidy of hepatocytes in the context of their capacity to proliferate and regenerate liver tissue. They demonstrate that polyploidy in the liver increases after partial hepatectomy. In addition, they show that the polyploid hepatocytes exhibit signs of oxidative injury and have a reduced proliferative ability when transplanted. Interestingly, the authors were able to recapitulate hepatocyte polyploidy in culture by subjecting cells to oxidative stress and mitogens. The finding that polyploidy is associated with oxidative injury and attenuates cell proliferation is particularly important given that polyploidy is a ubiquitous process and often occurs during microbial infection, pregnancy and oncogenesis. Furthermore, it has significant implications for therapeutic repopulation of the liver in inherited/malignant liver conditions.

How often - with the benefit of hindsight - do the discoveries of yesteryear seem predictable? And is the pace of research so frightening that we remember only the recent advances? Caveman believes that reviewing the past is an important part of today's science. He stands in awe of those who have gone before and urges scientists to reanalyse previous work in the light of current knowledge.