Cell cycle control: many ways to skin a cat

Thirty exponential cell divisions after fertilization would produce the number of cells in a baby mouse, but would not make a mouse. Sophisticated controls govern the cell cycle during development. These controls appear to play a central role in sculpting biological form. Rapid advances in our understanding of the machinery that drives the cell cycle provide a foundation for investigation of the molecular nature of cell cycle control in development. In this article, I emphasize that the design of the cell cycle machinery provides numerous inputs for regulation. I hope that the emphasis I have chosen will avert a tendency towards a narrow perception of cell cycle control.     

Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro

When added to living cells, sterols such as cholesterol and 25-hydroxycholesterol block the lateral movement of sterol regulatory element-binding proteins (SREBPs) into COPII-coated vesicles on endoplasmic reticulum (ER) membranes and thereby prevent the SREBPs from reaching the Golgi complex for processing to the mature forms that activate cholesterol synthesis. Sorting of SREBPs into COPII vesicles is mediated by Sar1 and the coat proteins Sec23 and Sec24. Here, we explore the mechanism of sterol inhibition in vitro through use of protein pull-down assays. We show that addition of cholesterol or 25-hydroxycholesterol to microsomal membranes in vitro blocks Sar1-dependent binding of the Sec23/24 complex to Scap, the SREBP escort protein. This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells. Sec23/24 binding to Scap requires the hexapeptide sequence MELADL located in a cytoplasmic loop of Scap. This hexapeptide acts as a sterol-regulated ER sorting signal. These studies define the biochemical parameters responsible for regulated sorting of an ER membrane protein into COPII-coated vesicles.     

Two ways to skin a cat: acyldepsipeptides antibiotics can kill bacteria through activation or inhibition of ClpP activity

Infection by Mycobacterium tuberculosis (Mtb) has had a devastating effect on the world population. Acyldepsipeptide antibiotics (ADEPs) are known to kill some bacteria by over activating the bacterial ClpP peptidase. ADEP antibiotics also target Mtb, with the assumption that uncontrolled ADEP‐activated proteolysis by ClpP is the common mode of killing. In this issue of Molecular Microbiology, Famulla, et al. now show that ADEP's effectiveness in mycobacteria is likely due to inhibition of ClpP‐dependent protease activity rather than activation. This finding of how the same antibiotic can kill bacteria by either inhibiting or activating proteases illustrates the utility of targeting these enzymes for sorely needed new antibiotics.     

A20: more than one way to skin a cat

In this issue of Molecular Cell, Skaug et al. (2011) propose a polyubiquitin-dependent, noncatalytic mechanism by which the deubiquitinase A20 inhibits IκB kinase and NF-κB activation.     

New ways to skin a kap: mechanisms for controlling nuclear transport.

Transport between the nucleus and the cytoplasm occurs through large macromolecular assemblies called nuclear pore complexes (NPCs). The NPC is traditionally viewed as a passive structure whose primary role is to provide an interface for the soluble transport machinery, the karyopherins and their cargos, to move molecules between these compartments. Recent work has challenged this view of the NPC and provides support for a dynamic structure that can modify its architecture to actively regulate nuclear transport.     

Auditory neuroscience: activating the cortex without sound

Sensory brain areas are usually characterized by their responses to external stimuli; however, neuroimaging studies have now shown that activation of auditory cortex occurs spontaneously and can be induced during silence by stimulus expectancy or mental imagery.     

Two ways to skin a plant: The analysis of root and shoot epidermal development in Arabidopsis

The post-embryonic architecture of higher plants is derived from the activity of two meristems that are formed in the embryo: the shoot meristem and the root meristem. The epidermis of the shoot is derived from the outermost layer of cells covering the shoot meristem through repeated anticlinal divisions. By contrast, the epidermis of the root is derived from an internal ring of cells, located at the centre of the root meristem, by a precise series of both periclinal and anticlinal divisions. Each epidermis has an independent origin. In Arabidopsis the mature shoot epidermis is composed of a small number of cell types: hair cells (trichomes), stomatal guard cells and other epidermal cells. In shoots, hairs take the form of branched trichomes that are surrounded at their base by a ring of accessory cells in a sheet of epidermal cells. The root epidermis is composed of two cell types: trichoblasts that form root hair cells and atrichoblasts that form non-hair cells. Mutations affecting both the patterning and the morphogenesis of cells in both shoot and root epidermis have recently been described. Most of these mutations affect development in a single epidermis, but at least one, ttg, is involved in development in both epidermal systems.     

Sex determination: ways to evolve a hermaphrodite

Most species of the nematode genus Caenorhabditis reproduce through males and females; C. elegans and C. briggsae, however, produce self-fertile hermaphrodites instead of females. These transitions to hermaphroditism evolved convergently through distinct modifications of germline sex determination mechanisms.     

Cohesin regulation: fashionable ways to wear a ring

Cohesin is a multiprotein complex, conserved from yeast to humans, that mediates sister chromatid cohesion. Its ring-shaped structure first suggested that it may perform its task by embracing the sister chromatids. The interaction of cohesin with chromatin is tightly regulated throughout the cell cycle, and several proteins contribute to cohesin loading and mobilization along DNA, establishment of cohesin-mediated cohesion, and removal of cohesin during mitosis. Recent studies suggest that distinct cohesin populations exist in different chromosomal regions and have particular requirements in their dynamic interaction with chromatin. In this review, I briefly summarize these studies and discuss their implications for current and future models of cohesin behavior.     

Anhydride and halogenated-anhydride trihalogenacetic acid interaction with thymidine-5'-phosphate: ways to new activating reagents in nucleotide phosphorylation reactions

The interaction of thymidine 5'-phosphate with trichloroacetic anhydride, trichloroacetyl chloride, and tribromoacetyl bromide was studied in dimethylformamide and acetonitrile in the presence of tertiary amines. The first two reactions gave the mixed anhydride of trichloroacetic and thymidylic acids (acyl phosphate) as the major product and P1, P2-dithymidine 5'-pyrophosphate as the byproduct. The third reaction proceeded by a more complicated mechanism and mainly led to substituted polyphosphates. The subsequent treatment of the reaction mixtures with morpholine resulted in thymidine 5'-phosphoromorpholidate in a high yield. The phosphorylating activities of the trichloroacetyl and tribromoacetyl phosphates were 77 and 89%, respectively.     

Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies

The establishment of a functional, integrated vascular system is instrumental for tissue growth and homeostasis. Without blood vessels no adequate nutrition and oxygen would be provided to cells, nor could the undesired waste products be efficiently removed. Blood vessels constitute therefore one of the largest and most complex body network whose assembly depends on the precise balance of growth factors acting in a complementary and coordinated manner with cells of several identities. However, the vessels that are crucial for life can also foster death, given their involvement in cancer progression towards malignancy and metastasis. Targeting tumor vasculature has thus arisen as an appealing anti-cancer therapeutic approach. Since the milestone achievements that vascular endothelial growth factor (VEGF) blockade suppressed angiogenesis and tumor growth in mice and prolonged the survival of cancer patients when administered in combination with chemotherapy, the clinical development of anti-VEGF(R) drugs has accelerated remarkably. FDA has approved the use of bevacizumab – a humanized monoclonal antibody against VEGF – in colorectal, lung and metastatic breast cancers in combination with standard chemotherapy. Additional broad-spectrum VEGF receptor tyrosine kinase inhibitors, such as sunitinib and sorafenib, are used in monotherapy for metastatic renal carcinoma, while sunitinib is also approved for imatinib resistant gastrointestinal stromal tumors and sorafenib for advanced stage hepatocellular carcinoma. Nevertheless, the survival benefit offered by VEGF(R) blockers, either as single agents or in combination with chemotherapy, is calculated merely in the order of months. Posterior studies in preclinical models have reported that despite reducing primary tumor growth, the inhibition of VEGF increased tumor invasiveness and metastasis. The clinical implications of these findings urge the need to reconcile these conflicting results. Anti-angiogenic therapy represents a significant step forth in cancer therapy and in our understanding of cancer biology, but it is also clear that we need to learn how to use it. What is the biological consequence of VEGF-blockade? Does VEGF inhibition starve the tumor to death – as initially postulated – or does it rather foster malignancy? Can anti-VEGF(R) therapy favor tumor vessel formation by VEGF-independent means? Tumors are very diverse and plastic entities, able to adapt to the harshest conditions; this is also reflected by the tumor vasculature. Lessons from the bench to the bedside and vice versa have taught us that the diversity of signals underlying tumor vessel growth will likely be responsive (or resistant) to distinct therapeutic approaches. In this review, we propose a reflection of the different strategies tumors use to grow blood vessels and how these can have impact on the (un)success of current anti-angiogenic therapies.