Differential lethality in developmental stages ofDrosophila following X-irradiation

Summary ADrosophila melanogaster line has been treated with ionizing radiations. The dose-response relationship has been studied upon separate treatment of male and female gametes. The results show that while the total survival is similar, at different developmental stages differences can be observed between progenies from treated male and female gametes. It is suggested that developmental patterns may affect the expression of induced mutations.     

NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia

The nuclear factor NF-kappaB and oncogenic Ras can alter proliferation in epidermis, the most common site of human cancer. These proteins are implicated in epidermal squamous cell carcinoma in mice, however, the potential effects of altering their function are uncertain. Whereas inhibition of NF-kappaB enhances apoptosis in certain tumours, blockade of NF-kappaB predisposes murine skin to squamous cell carcinoma. Because therapeutics inhibiting Ras and NF-kappaB pathways are being developed to treat human cancer, it is essential to assess the effects of altering these regulators. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. Here we show that in normal human epidermal cells both NF-kappaB and oncogenic Ras trigger cell-cycle arrest. Growth arrest triggered by oncogenic Ras can be bypassed by IkappaBalpha-mediated blockade of NF-kappaB, generating malignant human epidermal tissue resembling squamous cell carcinoma. Human cell tumorigenesis is dependent on laminin 5 and alpha6beta4 integrin. Thus, IkappaBalpha circumvents restraints on growth promotion induced by oncogenic Ras and can act with Ras to induce invasive human tissue neoplasia.     

Germline mutations in HRAS proto-oncogene cause Costello syndrome

Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors. We identified four heterozygous de novo mutations of HRAS in 12 of 13 affected individuals, all of which were previously reported as somatic and oncogenic mutations in various tumors. Our observations suggest that germline mutations in HRAS perturb human development and increase susceptibility to tumors.     

FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation

X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX). For 9 of the 66 MRX entries, the causative gene has been identified. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.