Family cancer syndromes: inherited deficiencies in systems for the maintenance of genomic integrity.
ABSTRACT Familial cancer syndromes have revealed important fundamental features regarding how all cancers arise through destabilization of the genome, such that somatic evolution can select for the disruption of critical cellular coordinating and regulatory features. The authors examine those cellular genes and systems whose normal role is to preserve genomic integrity and relate them to the genetic foundations of heritable cancers. By examining how these cellular systems normally function, how family cancer genes are able to affect the process of tumor progression can be learned. In so doing, a clearer picture of how sporadic cancers arise is additionally gained.
Article: The gamma134.5 protein of herpes simplex virus 1 has the structural and functional attributes of a protein phosphatase 1 regulatory subunit and is present in a high molecular weight complex with the enzyme in infected cells.[show abstract] [hide abstract]
ABSTRACT: The carboxyl-terminal domain of the gamma134.5 protein of the herpes simplex virus 1 binds to protein phosphatase 1alpha (PP1) and is required to prevent the shut-off of protein synthesis resulting from phosphorylation of the alpha subunit of eIF-2 by the double-stranded RNA-activated protein kinase. The corresponding domain of the conserved GADD34 protein homologous to gamma134.5 functionally substitutes for gamma134.5. This report shows that gamma134.5 and PP1 form a complex in the infected cells, that fractions containing this complex specifically dephosphorylate eIF-2alpha, and that both gamma134.5 and GADD34 proteins contain the amino acid sequence motif common to subunits of PP1 that is required for binding to the PP1 catalytic subunit. An oligopeptide containing this motif competes with gamma134.5 for binding to PP1. Substitution of Val193 and Phe195 in the PP1-binding motif abolished activity. These results suggest that the carboxyl-terminal domain of gamma134.5 protein has the structural and functional attributes of a subunit of PP1 specific for eIF-2alpha, that it has evolved to preclude shut-off of protein synthesis, and that GADD34 may have a similar function.Journal of Biological Chemistry 09/1998; 273(33):20737-43. · 4.77 Impact Factor
Genes & Development 05/1999; 13(7):768-85. · 11.66 Impact Factor
Article: The spindle checkpoint: a quality control mechanism which ensures accurate chromosome segregation.[show abstract] [hide abstract]
ABSTRACT: The centromere defines where on a chromosome the kinetochores assemble. Kinetochores, large protein structures, mediate chromosome segregation during mitosis and meiosis by performing three key functions. Firstly, kinetochores attach chromosomes to the microtubule spindle apparatus. Secondly, kinetochores co-ordinate microtubule dynamics to allow chromosomes to move along the spindle. Lastly, kinetochores generate the 'wait' signal which prevents anaphase onset until all the chromosomes are correctly aligned on the spindle. This signal forms part of the spindle checkpoint mechanism, a highly conserved cell cycle checkpoint which maintains the accuracy of the chromosome segregation process. This article provides a brief historical overview before focusing on some of the outstanding issues and more recent developments in the field.Chromosome Research 02/2004; 12(6):599-616. · 3.09 Impact Factor