Cloning of bovine GAP and its interaction with oncogenic ras p21

The plasma membrane-bound mammalian ras proteins of relative molecular mass 21,000 (ras p21) share biochemical and structural properties with other guanine nucleotide-binding regulatory proteins (G-proteins). Oncogenic ras p21 variants result from amino acid substitutions at specific positions that cause p21 to occur predominantly complexed to GTP in vivo. Recently, a GTPase activating protein (GAP) with cytosolic activity has been discovered that stimulates the GTPase activity of normal but not of oncogenic ras p21. GAP might be either a negative regulatory agent which acts further upstream in the regulatory pathway or the downstream target of ras p21. We have identified a protein from bovine brain with apparent relative molecular mass 125,000 that has GAP activity. Here, using pure GAP in a kinetic competition assay, we show that GAP interacts preferentially with the active GTP complexes of both normal and oncogenic Harvey (Ha) ras p21 compared with the inactive GDP complexes. We also report the cloning and sequencing of the complementary DNA for bovine GAP. Regions of GAP share amino acid similarity with the noncatalytic domain of adenylate cyclase from the yeast Saccharomyces cerevisiae and with regions conserved between phospholipase C-148, the crk oncogene product and the nonreceptor tyrosine kinases.     

Shotgun sample sequence comparisons between mouse and human genomes

A mixed 'clone-by-clone' and 'whole-genome shotgun' strategy will be used to determine the genomic sequence of the mouse. This method will allow a phase of rapid annotation of the contemporaneous human sequence draft, through whole-genome 'sample sequence comparisons'.     

Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing

We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.     

Calcium phosphate granules in muscle cells of Nephtys (Annelida, Polychaeta)--a novel skeleton?

Analyses of various marine polychaete worms (phylum Annelida) reveal that members of the family Nephtyidae are exceptional in containing very high concentrations of calcium and phosphorus. We report here that in the genus Nephtys, the two elements form rounded granules packing the sarcoplasmic core of obliquely striated muscle cells. Intracellular calcium granules rich in phosphorus are found throughout the animal kingdom and occur in a wide range of tissues. Although some examples of granules in muscle tissue have been recorded (as in Syllis proventriculus), as far as we are aware, none appears in the abundance found in Nephtys.     

Prelude to chemistry in industry

The Smith's Prize competition was established in Cambridge in 1768 by the will of Robert Smith (1689-1768). By fostering an interest in the study of applied mathematics, the competition contributed towards the success in mathematical physics that was to become the hallmark of Cambridge mathematics during the second half of the nineteenth century. Perceptions of Smith's intentions were to play a part in discussions about the content and balance of the mathematics curriculum, as may be seen in the Airy quotation in the title. In the twentieth century the competition acted to stimulate the formalization of Cambridge postgraduate research in mathematics. Throughout its existence the competition has played a significant role by providing a springboard for graduates considering an academic career and the majority of prize-winners have gone on to become professional mathematicians or physicists. In seeking the reasons behind the competition's success, attention has been paid to the life and work of Robert Smith, the intention behind his bequest, and the history of the competition from its origins until 1940.