Mutations in the gene encoding the adenovirus early region 1B 19,000-molecular-weight tumor antigen cause the degradation of chromosomal DNA

Abstract

The adenovirus mutant Ad2tslll has been previously shown to contain a mutation in the early region 2A gene encoding the single-stranded-DNA-binding protein that results in thermolabile replication of virus DNA and a mutation in early region 1 that causes degradation of intracellular DNA. A recombinant virus, Ad2cytlO6, has been constructed which contains the Adltslll early region 1 mutation and the wild-type early region 2A gene from adenovirus 5. This virus, like its parent Ad2tslll, has two temperature-independent phenotypes; first, it has the ability to cause an enhanced and unusual cytopathic effect on the host cell (cytocidal [cyt] phenotype) and second, it induces degradation of cell DNA (DNA degradation [deg] phenotype). The mutation responsible for these phenotypes is a single point mutation in the gene encoding the adenovirus early region 1B (ElB) 19,000-molecular-weight (19K) tumor antigen. This mutation causes a change from a serine to an asparagine in the 20th amino acid from the amino terminus of the protein. Three other mutants that affect the E1B 19K protein function have been examined. The mutants Ad21p5 and Ad5dl337 have both the cytocidal and DNA degradation phenotypes (cyt deg), whereas Ad21p3 has only the cytocidal phenotype and does not induce degradation of cell DNA (cyt deg'). Thus, the DNA degradation is not caused by the altered cell morphology. Furthermore, the mutant Ad5dl337 does not make any detectable E1B 19K protein product, suggesting that the absence of E1B 19K protein function is responsible for the mutant phenotypes. A fully functional E1B 19K protein is not absolutely required for lytic growth of adenovirus 2 in HeLa cells, and its involvement in transformation of nonpermissive cells to morphological variants is discussed.

Induction of apoptosis limits cytomegalovirus cross-species infection

“…The present study shows that certain β‐herpesviruses—large DNA viruses that replicate their genomes in the nucleus—induce apoptosis in cells of a foreign species, even though they can inhibit premature apoptosis in cells of their own species. A number of other viruses also depend on inhibition of apoptosis for normal replication, and consequently they encode potent cell death suppressors: Adenoviruses and γ‐herpesviruses are two prominent examples (Pilder et al , 1984; White et al , 1984; Altmann and Hammerschmidt, 2005). It is possible that the species restriction of these viruses also depends (in part) on their ability to inhibit cell death in cells of a foreign species, even if in the end more than one mechanism should turn out to be involved, as it appears to be the case for human CMV.…”

Differential distribution of the adenovirus E1A proteins and colocalization of E1A with the 70-kilodalton cellular heat shock protein in infected cells

“…Human 293 cells (11), which constitutively express adenovirus ElA and ElB gene prod-ucts, were grown in Dulbecco modified Eagle medium with 10% calf serum. The wild-type Ad2 was grown in infected HeLa cells and band purified by CsCl2 density gradient sedimentation as previously described (29,50). Adenovirus mutants containing the ElA 13S, 12S, and 9S cDNA genes in place of genomic ElA sequences (32,57) were kindly provided by E. Moran and B. Zerler (Cold Spring Harbor Laboratory).…”

Apoptosis in cancer

“…Signaling pro-caspases associate with Adenovirus mutants lacking the E1B 19K protein induce an specific adapter molecules that facilitate caspase activation by E1A-dependent 'cytocidal' phenotype that is associated with induced proximity (56)(57)(58). For example, caspase-9 associates 'degradation' of both viral and host-cell DNA (78,79). As a with Apaf-1, and oligomerization of this complex in the result, E1B mutant adenoviruses produce poor virus yield.…”