Search PubMed⌕ Search

Biomedical subjects

N Dyson

Publications and source records attributed to N Dyson.

47 records · Page 3Linked to original sources
PubMed1992

Adenovirus E1A targets key regulators of cell proliferation.

Studies of E1A support the notion that small DNA tumour viruses target cellular pathways at key points that are amenable to regulation. In the case of E1A, these targets appear to be points of control of cellular proliferation and, in particular, proteins that regulate the progression of cells from G0 and G1 phases of the cell cycle into the S phase. In several cases, recent studies have identified complexes between the viral targets and other cellular proteins. These interactions may provide insight not only into the mechanism of E1A mediated transformation but also into the control of proliferation in normal cells.

Adenovirus Early Proteins↗
PubMed1991

Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product.

The proteins encoded by the myc gene family are involved in the control of cell proliferation and differentiation, and aberrant expression of myc proteins has been implicated in the genesis of a variety of neoplasms. In the carboxyl terminus, myc proteins have two domains that encode a basic domain/helix-loop-helix and a leucine zipper motif, respectively. These motifs are involved both in DNA binding and in protein dimerization. In addition, myc protein family members share several regions of highly conserved amino acids in their amino termini that are essential for transformation. We report here that an N-terminal domain present in both the c-myc and N-myc proteins mediates binding to the retinoblastoma gene product, pRb. We show that the human papilloma virus E7 protein competes with c-myc for binding to pRb, indicating that these proteins share overlapping binding sites on pRb. Furthermore, a mutant Rb protein from a human tumour cell line that carried a 35-amino-acid deletion in its C terminus failed to bind to c-myc. Our results suggest that c-myc and pRb cooperate through direct binding to control cell proliferation.

Amino Acid Sequence↗
PubMed1991

Polyomavirus large T mutants affected in retinoblastoma protein binding are defective in immortalization.

To clarify the relationship between the various activities of the polyomavirus large T antigen and the contribution of this oncogene to neoplastic transformation, we constructed a series of mutants with small deletions or single-amino-acid substitutions in two separate regions of the protein. These sequences were targeted because they showed considerable similarity to conserved regions 1 and 2 of adenovirus E1A which are thought to be binding sites for the retinoblastoma gene product (pRB). The pRB-binding properties of the large T mutants were assessed with an in vitro coimmunoprecipitation assay. pRB binding was readily detected with wild-type large T, but coprecipitation was completely abolished by as little as a single amino acid substitution (Asp-141----Glu or Glu-146----Asp) in region 2 of the polyomavirus large T antigen. Mutants defective in pRB binding were unable to immortalize primary rat embryo fibroblasts, suggesting that association with pRB is an important component of immortalization mediated by polyomavirus large T. The mutations in region 1 affected pRB binding only marginally, yet some of them severely impaired immortalization, indicating that pRB binding may be essential but not sufficient for immortalization.

Amino Acid Sequence↗
PubMed1990

Cellular proteins that are targets for transformation by DNA tumour viruses.

Small DNA tumour viruses produce proteins that redirect cellular gene expression and growth control. The E1A polypeptides of adenovirus perform the functions of transcriptional activation and cellular transformation. These two functions are carried out by different domains within the E1A protein. The E1A protein associates with several cellular proteins, including the product of the retinoblastoma gene, pRb-1. Mutational analysis correlates transformation with the sites required for binding pRb and two other cellular proteins, p107 and a 300 kDa polypeptide. This correlation suggests that these proteins are targets for E1A-mediated transformation. Transforming proteins from other small DNA tumour viruses interact with pRb, raising the possibility that a common event in viral transformation is the inactivation of proteins that inhibit cellular proliferation. The role of the E1A-associated 60 kDa protein, p60, in transformation is being investigated. In the absence of E1A, p60 binds to the human homologue of the Schizosaccharomyces pombe cdc2 gene product, p34, to form a complex that has kinase activity that oscillates during the cell cycle. Ongoing studies of the effect of adenovirus infection, and specifically E1A expression, on this cellular kinase may provide clues to how E1A overcomes cell cycle controls and transforms cells.

Adenoviridae↗
PubMed1990

The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations.

The protein product of the retinoblastoma (RB) gene is thought to function in a pathway that restricts cell proliferation. Recently, transforming proteins from three different classes of DNA tumor viruses have been shown to form complexes with the RB protein. Genetic studies suggest that these interactions with the RB protein are important steps in transformation by these viruses. In order to understand better the function of the RB-viral oncoprotein complexes, we have mapped the regions of the RB protein that are necessary for these associations. Two non-contiguous regions of RB were found to be essential for complex formation with adenovirus E1A or SV40 large T antigen. These two regions are found between amino acids 393 and 572 and 646 and 772. Interestingly, these binding sites on RB overlap with the positions of naturally occurring, inactivating mutations of the RB gene. These results strongly suggest that these viral oncoproteins are targeting a protein domain that is an important site in the normal function of the RB protein.

Adenovirus Early Proteins↗
PubMed1989

Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.

The E7 proteins encoded by the human papillomaviruses (HPVs) associated with anogenital lesions share significant amino acid sequence homology. The E7 proteins of these different HPVs were assessed for their ability to form complexes with the retinoblastoma tumor suppressor gene product (p105-RB). Similar to the E7 protein of HPV-16, the E7 proteins of HPV-18, HBV-6b and HPV-11 were found to associate with p105-RB in vitro. The E7 proteins of HPV types associated with a high risk of malignant progression (HPV-16 and HPV-18) formed complexes with p105-RB with equal affinities. The E7 proteins encoded by HPV types 6b and 11, which are associated with clinical lesions with a lower risk for progression, bound to p105-RB with lower affinities. The E7 protein of the bovine papillomavirus type 1 (BPV-1), which does not share structural similarity in the amino terminal region with the HPV E7 proteins, was unable to form a detectable complex with p105-RB. The amino acid sequences of the HPV-16 E7 protein involved in complex formation with p105-RB in vitro have been mapped. Only a portion of the sequences that are conserved between the HPV E7 proteins and AdE1A were necessary for association with p105-RB. Furthermore, the HPV-16 E7-p105-RB complex was detected in an HPV-16-transformed human keratinocyte cell line.

Amino Acid Sequence↗
PubMed1989

The cellular 107K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus.

The association between the retinoblastoma protein (p105-RB) and either the large T antigen of SV40 or the E1A proteins of adenovirus is thought to be an important step in transformation by these viral oncogenes. E1A and large T antigen share a small region of amino acid homology that is necessary for high affinity binding with p105-RB. Mutations of this homology region were shown to reduce drastically the frequency of transformation mediated by the E1A or large T oncogenes. Previously, this small region in E1A was shown to be sufficient for interaction with a second cellular protein of 107,000 daltons (107K). Here we show that in human cells, the large T antigens of SV40 or JC virus also form complexes with 107K. Demonstration of complexes between 107K and the large T antigens of SV40 and JC virus suggests that these associations may represent another component of a common mechanism for transformation between adenoviruses and polyoma viruses.

Adenovirus Early Proteins↗
PubMed1989

The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product.

Deletions or mutations of the retinoblastoma gene, RB1, are common features of many tumors and tumor cell lines. Recently, the RB1 gene product, p105-RB, has been shown to form stable protein/protein complexes with the oncoproteins of two DNA tumor viruses, the adenovirus E1A proteins and the simian virus 40 (SV40) large T antigen. Neither of these viruses is thought to be associated with human cancer, but they can cause tumors in rodents. Binding between the RB anti-oncoprotein and the adenovirus or SV40 oncoprotein can be recapitulated in vitro with coimmunoprecipitation mixing assays. These assays have been used to demonstrate that the E7 oncoprotein of the human papilloma virus type-16 can form similar complexes with p105-RB. Human papilloma virus-16 is found associated with approximately 50 percent of cervical carcinomas. These results suggest that these three DNA viruses may utilize similar mechanisms in transformation and implicate RB binding as a possible step in human papilloma virus-associated carcinogenesis.

Adenovirus Early Proteins↗
PubMed1989

Cellular proteins that are targetted by DNA tumor viruses for transformation.

Tumor suppressor genes are genetic loci whose loss is associated with tumor development. Because the inactivation of these genes is a key feature in the genesis of certain tumors, it has been postulated that the protein products of tumor suppressor genes function in the negative regulation of cell proliferation. Tumor suppressor genes have been identified by genetic analysis either as loci associated with an inherited predisposition to certain tumors or by mapping studies that demonstrate allelic loss (reduction to homozygosity or loss of heterozygosity) during tumor development. The retinoblastoma gene, RB-1, was originally identified and cloned through its association with childhood retinoblastoma and is one of the best studied examples of the tumor suppressor genes. It has been shown that RB protein is also a key target for transformation by the oncogenes of several small DNA tumor viruses. The E1A proteins of adenovirus, the large T antigens of polyomaviruses, and E7 proteins of papillomaviruses all bind to pRB. Genetic studies of all three viruses have shown that any mutation that destroys binding to pRB also destroys the ability of these proteins to transform cells, suggesting that interaction with the RB gene product is a key event in viral transformation. In addition to interacting with pRB, the adenovirus E1A proteins and the polyomavirus large T antigens also bind to other cellular proteins. One of these, a protein with a molecular weight 0f 107,000 daltons, 107K, binds to E1A and large T at the same amino acid region as pRB, suggesting that the 107K and pRB proteins may have structural similarities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗