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Showing papers by "Novartis Foundation published in 2003"


Journal ArticleDOI
23 Oct 2003-Nature
TL;DR: The identities of these substrates reveal that Cdk1 employs a global regulatory strategy involving phosphorylation of other regulatory molecules as well as phosphorylated of the molecular machines that drive cell-cycle events.
Abstract: The events of cell reproduction are governed by oscillations in the activities of cyclin-dependent kinases (Cdks). Cdks control the cell cycle by catalysing the transfer of phosphate from ATP to specific protein substrates. Despite their importance in cell-cycle control, few Cdk substrates have been identified. Here, we screened a budding yeast proteomic library for proteins that are directly phosphorylated by Cdk1 in whole-cell extracts. We identified about 200 Cdk1 substrates, several of which are phosphorylated in vivo in a Cdk1-dependent manner. The identities of these substrates reveal that Cdk1 employs a global regulatory strategy involving phosphorylation of other regulatory molecules as well as phosphorylation of the molecular machines that drive cell-cycle events. Detailed analysis of these substrates is likely to yield important insights into cell-cycle regulation.

961 citations


Journal ArticleDOI
TL;DR: The structures presented here provide a basis for rationalizing the TSCP catalysis and reveal the possibility of the design of an inhibitor, and a new helix-loop-strand FAD binding motif characteristic of the enzymes in the T SCP family is identified.

83 citations


Journal ArticleDOI
TL;DR: Data show that Dd-STATc functions as a transcriptional activator in a stress-response pathway and the pharmacological evidence, at least, is consistent with cGMP acting as a second messenger.
Abstract: The Dictyostelium stalk cell inducer differentiation-inducing factor (DIF) directs tyrosine phosphorylation and nuclear accumulation of the STAT (signal transducer and activator of transcription) protein Dd-STATc. We show that hyperosmotic stress, heat shock and oxidative stress also activate Dd-STATc. Hyperosmotic stress is known to elevate intracellular cGMP and cAMP levels, and the membrane-permeant analogue 8-bromo-cGMP rapidly activates Dd-STATc, whereas 8-bromo-cAMP is a much less effective inducer. Surprisingly, however, Dd-STATc remains stress activatable in null mutants for components of the known cGMP-mediated and cAMP-mediated stress-response pathways and in a double mutant affecting both pathways. Also, Dd-STATc null cells are not abnormally sensitive to hyperosmotic stress. Microarray analysis identified two genes, gapA and rtoA , that are induced by hyperosmotic stress. Osmotic stress induction of gapA and rtoA is entirely dependent on Dd-STATc. Neither gene is inducible by DIF but both are rapidly inducible with 8-bromo-cGMP. Again, 8-bromo-cAMP is a much less potent inducer than 8-bromo-cGMP. These data show that Dd-STATc functions as a transcriptional activator in a stress-response pathway and the pharmacological evidence, at least, is consistent with cGMP acting as a second messenger.

46 citations


Journal ArticleDOI
Lisa Melton1
24 Apr 2003-Nature
TL;DR: Lisa Melton examines the early steps towards personal genotyping, which aims to derive useful data from the human genome sequence by identifying the “missing pieces” in the sequence.
Abstract: Extracting useful data from the human genome sequence is a major challenge. Lisa Melton examines the early steps towards personal genotyping.

32 citations


Journal ArticleDOI
TL;DR: A synthesis of a previously unknown indole derivative is presented and conditions are presented for the Pd-catalyzed elaboration of one of the "diversity generating elements" of this important pharmacophore.
Abstract: A synthesis of a previously unknown indole derivative is presented. The route reported herein allows for the preparation of multihundred gram quantities of material without any chromatographic purification. Conditions are presented for the Pd-catalyzed elaboration of one of the “diversity generating elements” of this important pharmacophore.

11 citations