Biochemical properties of a transforming nonkaryophilic T antigen of SV40

Fischer-Fantuzzi, L; Scheidtmann, Karl Heinz; Vesco, Cesare

doi:10.1016/0042-6822(86)90010-3

Cited by 19 publications

(20 citation statements)

References 41 publications

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“…Similarly, the carboxyterminal variable region and host-range domains are dispensable for focus induction (Pipas et al, 1983;Zhu et al, 1992). Surprisingly, even nuclear localization signal (NLS) mutants induce transformation of established cell lines, although these mutants are defective when tested on primary cells (Lanford et al, 1985;Fischer-Fantuzzi et al, 1986). Care must be taken in interpreting these results.…”

Section: T Antigens Elicit Transformation By Targeting Cellular Proteinsmentioning

confidence: 99%

SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation

2005

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DNA tumor viruses such as simian virus 40 (SV40) express dominant acting oncoproteins that exert their effects by associating with key cellular targets and altering the signaling pathways they govern. Thus, tumor viruses have proved to be invaluable aids in identifying proteins that participate in tumorigenesis, and in understanding the molecular basis for the transformed phenotype. The roles played by the SV40-encoded 708 aminoacid large T antigen (T antigen), and 174 amino acid small T antigen (t antigen), in transformation have been examined extensively. These studies have firmly established that large T antigen's inhibition of the p53 and Rbfamily of tumor suppressors and small T antigen's action on the pp2A phosphatase, are important for SV40-induced transformation. It is not yet clear if the Rb, p53 and pp2A proteins are the only targets through which SV40 transforms cells, or whether additional targets await discovery. Finally, expression of SV40 oncoproteins in transgenic mice results in effects ranging from hyperplasia to invasive carcinoma accompanied by metastasis, depending on the tissue in which they are expressed. Thus, the consequences of SV40 action on these targets depend on the cell type being studied. The identification of additional cellular targets important for transformation, and understanding the molecular basis for the cell type-specific action of the viral T antigens are two important areas through which SV40 will continue to contribute to our understanding of cancer.

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Section: T Antigens Elicit Transformation By Targeting Cellular Proteinsmentioning

confidence: 99%

SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation

2005

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“…According to these data a major N-terminal region ranging from amino acid 1 to 114 appears to be dispensable for the formation of fast sedimenting oligomers of T antigen. This assumption is strongly supported by the observation that aggregates of the DZprotein are typically sensitive to treatment with 20 mM EDTA like wild-type T antigen [ 18,191. To amplify further the results obtained with the DZ-protein, we selected the deletion mutant CTSVl [21] which codes for T antigen lacking amino acids 1 lo-152 and overlaps the N-terminal defect of the DZprotein (l-l 14). To analyse T antigen encoded by CTSVl for oligomerization we used a CTSVl transformed mouse cell line CTM [15].…”

Section: Resultsmentioning

confidence: 99%

Regions of SV40 large T antigen necessary for oligomerization and complex formation with the cellular oncoprotein p53

et al. 1986

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The simian virus 40 (SV40) T antigen is composed of 708 amino acids and forms monomers and various oligomers and, in small amounts, heterologous complexes with the cellular oncoprotein p53 (T‐p53). Using SV40 mutants coding for T antigen fragments which are either deleted in the N‐terminal half or truncated by various lengths at the C‐terminal end, we found that a region between amino acids 114 and 152 and a C‐terminal region up to amino acid 669 are essential for the formation of high Mr oligomers of T antigen. Furthermore, only the C‐terminal end up to amino acid 669 is essential for T‐p53 complex formation but not the N‐terminus up to amino acid 152.

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“…Another possible interpretation is that the NKLT and YLT3 activities might depend on only a few molecules that have somehow diffused into the nucleus, while the mass of observable oncoprotein would be superfluous in this respect. This possibility is hard to exclude, because diffusion below 1 or 2% of the total is nearly impossible to detect, even when relying on the distinctive pattern of NKLT phosphorylation (11). It is not a very likely possibility, however, because different studies indicate that low oncoprotein levels prevent transformation by SV40 (1,36,49), and furthermore, the reduced activity of the nuclear NKLT variant in CS cells suggests that the presence of NKLT in the cytoplasm is not functionally irrelevant.…”

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confidence: 90%

“…We previously characterized a mutant of the SV40 large T antigen which lacks the normal large-T-antigen karyophily and accumulates in the cytoplasm (because of a natural deletion in the gene, which was originally found as a viral insertion in the DNA of transformed cells) (12). This nonkaryophilic large T antigen (NKLT) lacks amino acids 110 through 152 of the SV40 large T antigen, cannot bind to SV40 origin DNA (11,12), is phosphorylated in vivo at only two sites (11), and predominantly forms dimers and cytoplasmic complexes * Corresponding author.…”

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confidence: 99%

“…Mutagenesis was carried out by inserting the synthetic sequences indicated below at a Bcll site (corresponding to SV40 nt 2770) of pACTSV2. This is a previously described construct (11) containing an entire SV40 genome carrying the NKLT deletion (SV40 nt 4362 to 4490) cloned in pAT153; this deletion is the only difference between the wt large T antigen and the NKLT gene. We used two pairs of synthetic 24-nt oligomers, each pair of which was constituted by complementary sequences except for 4 unpaired bases (GATC) at the 5' end.…”

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Cell-dependent efficiency of reiterated nuclear signals in a mutant simian virus 40 oncoprotein targeted to the nucleus.

Fischer-Fantuzzi¹,

Vesco²

1988

Mol. Cell. Biol.

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We investigated the requisites for, and functional consequences of, the relocation to the nucleus of a transforming nonkaryophilic mutant of the simian virus 40 large T antigen (a natural deletion mutant lacking an internal large-T-antigen domain that includes the signal for nuclear transport). Synthetic oligonucleotides were used to obtain gene variants with one or more copies of the signal-specifying sequence inserted near the gene 3' end, in a region dispensable for the main large-T-antigen functions. The analysis of stable transfectant populations showed that mouse NIH 3T3 ceUls, rat embryo fibroblasts, and simian CS cells (a subclone of CV1 ceUls) differed considerably in their ability to localize some variant molecules into the nucleus. CS cells were always the most efficient, and NIH 3T3 ceUs were the least efficient. The nuclear localization improved either with reiteration of the signal or with a left-flank modification of the signal amino acid context. Three signals appeared to be necessary and sufficient, even in NIH 3T3 ceUs, to obtain a nuclear accumulation comparable to that of wild-type simian virus 40 large T antigen; other signal-cell combinations caused a large variability in subcellular localization among ceUls of the same population, as if the nuclear uptake of some molecules depended on individual cel states. The effect of the modified location on the competence of the protein to alter cell growth was examined by comparing the activity of variants containing either the normal signal or a signal with a mutation (corresponding to large-T-antigen amino acid 128) that prevented nuclear transport. It was found that the nuclear variant was slightly more active than the cytoplasmic variants in rat embryo fibroblasts and NIH 3T3 cells and was notably less active in CS cells.The nuclear localization of a number of eucaryotic proteins is known to depend on the presence in their polypeptide chains of determinants that vary in sequence and number; these are generally referred to as nuclear signals (3,

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Biochemical properties of a transforming nonkaryophilic T antigen of SV40

Cited by 19 publications

References 41 publications

SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation

SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation

Regions of SV40 large T antigen necessary for oligomerization and complex formation with the cellular oncoprotein p53

Cell-dependent efficiency of reiterated nuclear signals in a mutant simian virus 40 oncoprotein targeted to the nucleus.

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