Clonal expansion of p53 mutant cells is associated with brain tumour progression.

Tumour progression is a fundamental feature of the biology of cancer. Cancers do not arise de novo in their final form, but begin as small, indolent growths, which gradually acquire characteristics associated with malignancy. In the brain, for example, low-grade tumours (astrocytomas) evolve into faster growing, more dysplastic and invasive high-grade tumours (glioblastomas). To define the genetic events underlying brain tumour progression, we analysed the p53 gene in ten primary brain tumour pairs. Seven pairs consisted of tumours that were high grade both at presentation and recurrence (group A) and three pairs consisted of low-grade tumours that had progressed to higher grade tumours (group B). In group A pairs, four of the recurrent tumours contained a p53 gene mutation; in three of them, the same mutation was found in the primary tumour. In group B pairs, progression to high grade was associated with a p53 gene mutation. A subpopulation of cells were present in the low-grade tumours that contained the same p53 gene mutation predominant in the cells of the recurrent tumours that had progressed to glioblastoma. Thus, the histological progression of brain tumours was associated with a clonal expansion of cells that had previously acquired a mutation in the p53 gene, endowing them with a selective growth advantage. These experimental observations strongly support Nowell's clonal evolution model of tumour progression.     

Specific low-affinity recognition of major histocompatibility complex plus peptide by soluble T-cell receptor.

The T-cell receptor is necessary and sufficient for recognition of peptides presented by major histocompatibility complex molecules. Other adhesion molecules, like CD4 or CD8, play an auxiliary role in antigen recognition by T cells. Here we analyse T-cell receptor (TCR) binding using a soluble rather than a cell-bound receptor molecule. A TCR-immunoglobulin chimaera is constructed with the variable and the first constant regions of both the TCR alpha- and beta-chains linked to the immunoglobulin light-chain constant regions. This soluble TCR is expressed, assembled and secreted as an alpha beta heterodimer by a myeloma cell line transfected with the recombinant genes. Furthermore, the soluble TCR is biologically active: it specifically inhibits antigen-dependent activation of the relevant T-cell clones and thus discriminates between proper and irrelevant peptides presented by major histocompatibility complex molecules.     

Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding.

The main stress proteins of Escherichia coli function in an ordered protein-folding reaction. DnaK (heat-shock protein 70) recognizes the folding polypeptide as an extended chain and cooperates with DnaJ in stabilizing an intermediate conformational state lacking ordered tertiary structure. Dependent on GrpE and ATP hydrolysis, the protein is then transferred to GroEL (heat-shock protein 60) which acts catalytically in the production of the native state. This sequential mechanism of chaperone action may represent an important pathway for the folding of newly synthesized polypeptides.     

Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.

Proteolipid protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.     

A functional barrier to movement of lipids in polarized neurons.

In polarized neurons, axons and dendrites perform different functions, which are reflected in their different molecular organization. Studies on the sorting of viral and endogenous glycoproteins in epithelial cells and hippocampal neurons suggest that there may be similarities in the mechanism of sorting in these two cell types. The mechanisms that maintain the distinct composition of the two plasma membrane domains in these two cell types must, however, be different. We have proposed the existence of a functional barrier at the axonal hillock/initial segment which prevents the intermixing of membrane constituents. Here we test this hypothesis by fusing liposomes containing fluorescent phospholipids into the plasma membrane of polarized hippocampal cells in culture. Fusion was induced by lowering the pH and mediated by influenza virus haemagglutinin expressed on the axonal surface of neurons infected with fowl plague virus. Labelling was found exclusively on axons after fusion. Although the fused lipids were mobile on the axonal membrane, no labelling was detected on the cell body and dendritic surfaces. These results suggest that there is a diffusion barrier at the axonal hillock/initial segment which maintains the compositional differences between the axonal and somatodendritic domains.     

Communal nesting patterns in mice implicate MHC genes in kin recognition.

House mice (Mus musculus domesticus) form communal nests and appear to nurse each other's pups indiscriminately. Communal nesting probably functions to reduce infanticide, but it also makes females vulnerable to exploitation if nursing partners fail to provide their fair share of care. Kinship theory predicts that females will preferentially form communal nests with relatives to minimize exploitation and further increase inclusive fitness. Here we provide evidence from seminatural populations that females prefer communal nesting partners that share allelic forms of major histocompatibility complex genes. Such behaviour would lead to the selection of close relatives as communal nesting partners. Although criteria for the demonstration of kin recognition are currently embroiled in controversy, this is the first vertebrate study to meet Grafen's restrictive requirements: discrimination is based on genetic similarity at highly polymorphic loci, incidental correlations due to relatedness are experimentally controlled, and strong reasons exist for expecting the assayed behaviour to be kin-selected.     

Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a major health problem, affecting 5% of the world population. Genetic factors are important in NIDDM, but the mechanisms leading to glucose intolerance are unknown. Genetic linkage has been investigated in multigeneration families to localize, and ultimately identify, the gene(s) predisposing to NIDDM. Here we report linkage between the glucokinase locus on chromosome 7p and diabetes in 16 French families with maturity-onset diabetes of the young, a form of NIDDM characterized by monogenic autosomal dominant transmission and early age of onset. Statistical evidence of genetic heterogeneity was significant, with an estimated 45-95% of the 16 families showing linkage to glucokinase. Because glucokinase is a key enzyme of blood glucose homeostasis, these results are evidence that a gene involved in glucose metabolism could be implicated in the pathogenesis of NIDDM.     

Novel major archaebacterial group from marine plankton.

Marine bacteria often dominate the plankton biomass and are responsible for much of the cycling of organic matter, but bacterial diversity is poorly understood because conventional identification methods (requiring culturing) miss about 99% of the organisms. Recent advances permit characterization of microbial communities by analysis of 16S ribosomal RNA gene sequences directly from biomass without the need to culture the organisms; such studies from surface ocean samples have found only eubacteria, not archaebacteria (or Archaea), which are profoundly different. Here we report 16S rRNA sequences obtained from Pacific Ocean bacterioplankton samples collected from depths of 100 m and 500 m. Among these we found sequences only distantly related to those of any organisms previously characterized by 16S rRNA sequences, with similarities to the nearest such relatives (extreme thermophiles) approximately the same as those between animals and plants. We suggest that these sequences are from a previously undescribed archaebacterial group that may have diverged from the ancestors of characterized organisms very early in evolution.