RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.     

春潮

春天来了,万物复苏,三家平时不动声色的超级豪华轿车制造商不约而同地有了行动。一时间,宾利出了四门车大陆 Flying Spur(Continental Flying Spur),劳斯莱斯加长了幻影(Phantom),迈巴赫(Maybach)为3月开幕的日内瓦车展带来了新开发的迈巴赫57特别版     

Structure of a bacterial 30S ribosomal subunit at 5.5 A resolution.

The 30S ribosomal subunit binds messenger RNA and the anticodon stem-loop of transfer RNA during protein synthesis. A crystallographic analysis of the structure of the subunit from the bacterium Thermus thermophilus is presented. At a resolution of 5.5 A, the phosphate backbone of the ribosomal RNA is visible, as are the alpha-helices of the ribosomal proteins, enabling double-helical regions of RNA to be identified throughout the subunit, all seven of the small-subunit proteins of known crystal structure to be positioned in the electron density map, and the fold of the entire central domain of the small-subunit ribosomal RNA to be determined.     

The spread of HIV-1 in Africa: sexual contact patterns and the predicted demographic impact of AIDS

The spread of HIV-1 in Africa is examined here in the light of recent information on the main epidemiological and behavioural determinants of transmission. Mathematical models incorporating demographic, epidemiological and behavioural processes are used to assess the potential demographic impact of the disease AIDS. These analyses highlight the significance of patterns of sexual behaviour, and in particular networks of sexual contact, on the predicted spread of infection. Current data reveal substantial variations in the degree of spread between and in countries, but new analyses support earlier predictions that in the worst-afflicted areas AIDS is likely to change population growth rates from positive to negative values in a few decades.     

风险与无常

在科学的边界上我们并不是始终能知道将会发生些什么?     

Transmission dynamics of HIV infection

Simple mathematical models of the transmission dynamics of human immunodeficiency virus help to clarify some of the essential relations between epidemiological factors, such as distributed incubation periods and heterogeneity in sexual activity, and the overall pattern of the AIDS epidemic. They also help to identify what kinds of epidemiological data are needed to make predictions of future trends.     

Chemical excitability of axons: excitatory and inhibititory effects of putative neurotransmitters and modulators on frog sciatic nerves.

The microiontophoretic administration of putative neuromodulators (acetylcholine, norepinephrine, dopamine, 2-phenylethylamine, tryptamine, histamine) triggered firing or inhibited on-going activity in isolated frog sciatic nerves.