Since the discovery of ING1 class II tumor suppressors in 1996, five different ING genes (ING1 to ING5) encoding proteins with highly conserved plant homeodomain (PHD) motifs and several splicing isoforms of the ING1 and ING2 gene have been identified. The ING family functions in DNA repair and apoptosis in response to UV damage through binding to proliferating cell nuclear antigen (PCNA); chromatin remodeling and regulation of gene expression through regulating and/or targeting histone acetyltransferase/deacetylase (HAT/HDAC) activities; binding targets of rare phosphatidylinositol phosphates (PtdInsPs) that function in DNA damage-initiated stress signaling; and regulating brain tumor angiogenesis through transcriptional repression of NF-KB-responsive genes. To elucidate the evolutionary history of ING proteins and summarize what is known about regions highly conserved in the ING family members, we have examined the sequences and phylogenetic relationships of ING proteins across taxonomically diverse organisms. We have identified novel ING family members in rats, frogs, fish, mosquitoes, fruit flies, worms, fungi, and plants. We have also clarified the naming and classification of ING proteins based on our phylogenetic analysis to allow better understanding of the ING protein family. Using sequence similarities, we have identified novel regions and motifs of unknown function that are conserved across family members. An evolutionary history for the ING family of PHD finger proteins is presented that indicates that five ING genes are present in vertebrates. Three of these may be paralogs of ING genes found in arthropods, whereas nematodes, fungi, and green plants contain ING genes that have general features of the vertebrate ING family.
SUMMARY Cowpox virus is considered ancestral to orthopoxviridae since CPXV encodes the most extensive array of putative immunomodulators that likely contribute to its wide host range including zoonotic infections in humans. Unlike vaccinia virus, CPXV prevents stimulation of CD8+ T cells and this correlated with retention of MHC-I in the endoplasmic reticulum by CPXV203. However, deletion of CPXV203 did not restore MHC-I transport or T cell stimulation. Here, we demonstrate that the type II transmembrane protein, CPXV012, additionally interferes with MHC-I/peptide complex formation by inhibiting peptide translocation by TAP. CPXV012 thus represents the first non-herpesvial TAP inhibitor. Importantly, human and mouse MHC-I transport and T cell stimulation was restored upon deletion of both CPXV012 and CPXV203 suggesting that these unrelated proteins independently mediate T cell evasion in multiple hosts. Interestingly, CPXV012 is a truncated version of a putative NK cell ligand indicating that poxviral gene fragments can encode new unexpected functions.
The candidate tumor suppressor gene, ING1, encodes several protein isoforms as a result of alternative splicing that may possess agonistic and antagonistic roles in the control of cell proliferation and apoptosis. Recently a related gene, ING2, was isolated in human whose expression is increased in adenocarcinomas. Little is known about the cellular function and regulation of these ING family members, but the fact that ING proteins contain a plant homeodomain finger suggests that these proteins may modulate transcription factor-mediated pathways. To elucidate how ING may interact in different tissues to modulate function, we used amphibian metamorphosis as a model system in which a single stimulus, thyroid hormone (TH), initiates tissue-specific proliferation, differentiation, and apoptosis. We have isolated the first Xenopus laevis ING2 and demonstrate that transcript levels increase in response to TH treatment. We provide evidence for the existence of splice variants that are differentially expressed in tissues with different TH-induced fates. Western blots using an antibody directed against the highly conserved C-terminal end of ING proteins reveal a tissue-specific pattern of ING isoform expression in adult Xenopus tissues. Analyses of premetamorphic tadpole tissues show a TH-induced accumulation of ING proteins in tail, whereas the levels in the leg are not affected. This TH-induced accumulation is also observed in serum-free tail organ cultures and is prevented by inhibitors of tail apoptosis. Therefore, this work presents the first link between ING expression and a hormonally regulated nuclear transcription factor-mediated apoptotic response opening the possibility that ING family members may be involved in transducing the signal initiated by TH that determines cell fate. 2 (The former gene has been referred to as INGL and ING2, whereas the latter has been referred to as ING2 but is distinct from the former.) We will refer to the former gene as ING2 and the latter as ING4 to avoid confusion. A more distantly related ING3 mRNA encoding a putative 47-kDa protein has also been reported in mouse (GenBank TM accession number AY007790).3 ING2 maps to a different chromosome than ING1. Its putative protein product is predicted to also be 33 kDa in size and has 54% sequence identity to p33 ING1b (19,21 ING proteins belong to a family of plant homeodomain (PHD)
Background: Profilins are critical to cytoskeletal dynamics in eukaryotes; however, little is known about their viral counterparts. In this study, a poxviral profilin homolog, ectromelia virus strain Moscow gene 141 (ECTV-PH), was investigated by a variety of experimental and bioinformatics techniques to characterize its interactions with cellular and viral proteins.
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