10 research outputs found
Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.
Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP
SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML
The E1B-55K product from human adenovirus is a substrate of the small ubiquitin-related modifier (SUMO)-conjugation system. SUMOylation of E1B-55K is required to transform primary mammalian cells in cooperation with adenovirus E1A and to repress p53 tumour suppressor functions. The biochemical consequences of SUMO1 conjugation of 55K have so far remained elusive. Here, we report that E1B-55K physically interacts with different isoforms of the tumour suppressor protein promyelocytic leukaemia (PML). We show that E1B-55K binds to PML isoforms IV and V in a SUMO1-dependent and -independent manner. Interaction with PML-IV promotes the localization of 55K to PML-containing subnuclear structures (PML-NBs). In virus-infected cells, this process is negatively regulated by other viral proteins, indicating that binding to PML is controlled through reversible SUMOylation in a timely coordinated manner. These results together with earlier work are consistent with the idea that SUMOylation regulates targeting of E1B-55K to PML-NBs, known to control transcriptional regulation, tumour suppression, DNA repair and apoptosis. Furthermore, they suggest that SUMO1-dependent modulation of p53-dependent growth suppression through E1B-55K PML-IV interaction has a key role in adenovirus-mediated cell transformation
Transformation and oncogenicity by Adenoviruses
Adenoviruses have attracted considerable attention since it was discovered by
TRENTIN et all. and HUEBNER et al. that certain species (formerly called serotypes) are oncogenic when injected into newborn
hamsters. Since then, adenoviruses have been used extensively as a model for studies on tumor induction in vivo and. cell transformation in vitro. Together with the small papovaviruses they have played an important role in fundamental cancer research and have provided invaluable tools for studies on the organization and the expression of eukaryotic genes. The introduction of new techniques of DNA sequencing, molecular cloning, and DNA transfection in the past few years have furter contributed to a rapid development of adenovirus research in all its diverse aspects