SV40 Large T Antigen Functions at Two Distinct Steps in Virion Assembly

Spence, Susan L.; Pipas, James M.

doi:10.1006/viro.1994.1524

Cited by 35 publications

(23 citation statements)

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“…The mature virion encapsulates the viral DNA molecule and has a sedimentation coefficient of 240S in a sucrose density gradient (42). Developing virions composed of chromatin and some VP polypeptides have less-dense sedimentation coefficients ranging between 100 and 150S (221,222). Both genetic and biochemical data indicate that a wild-type T antigen is required for virion assembly for at least two independent steps of virion maturation.…”

Section: J Domain and Virion Assemblymentioning

confidence: 99%

“…Some T-antigen mutants in either the extreme carboxyl-VOL. 66,2002 MOLECULAR CHAPERONE FUNCTIONS OF T ANTIGEN 193 terminal host range (HR) specificity function or the J domain (L19F,P28S) replicate DNA and produce VP1 to -3 but fail to assemble mature virions (221,222). Both mutants produce immature capsid intermediates that migrate at unique lower densities in a sucrose gradient.…”

Section: J Domain and Virion Assemblymentioning

confidence: 99%

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T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis

Sullivan

Pipas

2002

Microbiol Mol Biol Rev

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224

228

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Simian virus 40 (SV40) is a small DNA tumor virus that has been extensively characterized due to its relatively simple genetic organization and the ease with which its genome is manipulated. The large and small tumor antigens (T antigens) are the major regulatory proteins encoded by SV40. Large T antigen is responsible for both viral and cellular transcriptional regulation, virion assembly, viral DNA replication, and alteration of the cell cycle. Deciphering how a single protein can perform such numerous and diverse functions has remained elusive. Recently it was established that the SV40 T antigens, including large T antigen, are molecular chaperones, each with a functioning DnaJ domain. The molecular chaperones were originally identified as bacterial genes essential for bacteriophage growth and have since been shown to be conserved in eukaryotes, participating in an array of both viral and cellular processes. This review discusses the mechanisms of DnaJ/Hsc70 interactions and how they are used by T antigen to control viral replication and tumorigenesis. The use of the DnaJ/Hsc70 system by SV40 and other viruses suggests an important role for these molecular chaperones in the regulation of the mammalian cell cycle and sheds light on the enigmatic SV40 T antigen—a most amazing molecule

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Section: J Domain and Virion Assemblymentioning

confidence: 99%

Section: J Domain and Virion Assemblymentioning

confidence: 99%

T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis

Sullivan

Pipas

2002

Microbiol Mol Biol Rev

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224

228

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“…Aside from LT and sT, other T-antigen isoforms, such as middle T antigen (MT) and 17kT/57kT, may be present and are virus specific. LT has pleiotropic functions that include initiation and maintenance of viral DNA replication, regulation of early and late genes transcription, and virion assembly (11,21,36,43,51,52,54). Expression of LT also leads to the transformation of susceptible cell lines mediated in part by functional regions such as the DnaJ, pocket protein binding, and p53 binding domains that target growth-suppressing and cell cycle regulatory proteins (53).…”

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confidence: 99%

The Minimum Replication Origin of Merkel Cell Polyomavirus Has a Unique Large T-Antigen Loading Architecture and Requires Small T-Antigen Expression for Optimal Replication

Kwun

Guastafierro

Shuda

et al. 2009

J Virol

135

218

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Merkel cell polyomavirus (MCV) is a recently discovered human polyomavirus causing the majority of human Merkel cell carcinomas. We mapped a 71-bp minimal MCV replication core origin sufficient for initiating eukaryotic DNA replication in the presence of wild-type MCV large T protein (LT). The origin includes a poly(T)-rich tract and eight variably oriented, GAGGC-like pentanucleotide sequences (PS) that serve as LT recognition sites. Mutation analysis shows that only four of the eight PS are required for origin replication. A single point mutation in one origin PS from a naturally occurring, tumor-derived virus reduces LT assembly on the origin and eliminates viral DNA replication. Tumor-derived LT having mutations truncating either the origin-binding domain or the helicase domain also prevent LT-origin assembly. Optimal MCV replication requires coexpression of MCV small T protein (sT), together with LT. An intact DnaJ domain on the LT is required for replication but is dispensable on the sT. In contrast, PP2A targeting by sT is required for enhanced replication. The MCV origin provides a novel model for eukaryotic replication from a defined DNA element and illustrates the selective pressure within tumors to abrogate independent MCV replication.Unlike human cellular DNA replication origins, polyomavirus replication origins are discrete and well defined and yet retain many features of eukaryotic cellular origins. For this reason, polyomavirus replication origins, particularly the simian virus 40 (SV40) origin, have been used as easily tractable models to define eukaryotic replication requirements (1).Polyomaviruses are small, double-stranded DNA viruses with circular genomes functionally divided into coding and noncoding regions (10). The early coding region for all polyomaviruses encodes large tumor (LT) and small T (sT) antigens that serve as viral oncoproteins and a late coding region that produces viral structural proteins. Aside from LT and sT, other T-antigen isoforms, such as middle T antigen (MT) and 17kT/57kT, may be present and are virus specific. LT has pleiotropic functions that include initiation and maintenance of viral DNA replication, regulation of early and late genes transcription, and virion assembly (11,21,36,43,51,52,54). Expression of LT also leads to the transformation of susceptible cell lines mediated in part by functional regions such as the DnaJ, pocket protein binding, and p53 binding domains that target growth-suppressing and cell cycle regulatory proteins (53). In addition, sT has been shown to play an important role in LT mediated cell transformation in SV40 (3,6,7,24,38) and has been reported to increase virus replication efficiency in JC virus (JCV) (39).Merkel cell polyomavirus (MCV) was recently identified by digital transcriptome subtraction (23) as a new human polyomavirus present in ϳ80% of Merkel cell carcinoma (MCC) (22). Preferential detection of MCV in MCC has subsequently been confirmed in a variety of different settings (4,17,29,58). Similar to JCV and BK virus, this n...

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“…Mutations within the J-domain region of T antigen affect diverse viral functions including DNA replication, transcriptional regulation, virion assembly, and tumorigenesis (39,41,47,48). Recent reports suggest a role for the T antigen-hsc70 association in stimulating the degradation of the tumor suppressors p107 and p130 (26,49).…”

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confidence: 99%

The Amino-Terminal Transforming Region of Simian Virus 40 Large T and Small t Antigens Functions as a J Domain

Srinivasan

McClellan

Vartikar

et al. 1997

Molecular and Cellular Biology

213

268

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Simian virus 40 (SV40) encodes two proteins, large T antigen and small t antigen that contribute to virus-induced tumorigenesis. Both proteins act by targeting key cellular regulatory proteins and altering their function. Known targets of the 708-amino-acid large T antigen include the three members of the retinoblastoma protein family (pRb, p107, and p130), members of the CBP family of transcriptional adapter proteins (cap-binding protein [CBP], p300, and p400), and the tumor suppressor p53. Small t antigen alters the activity of phosphatase pp2A and transactivates the cyclin A promoter. The first 82 amino acids of large T antigen and small t antigen are identical, and genetic experiments suggest that an additional target(s) important for transformation interacts with these sequences. This region contains a motif similar to the J domain, a conserved sequence found in the DnaJ family of molecular chaperones. We show here that mutations within the J domain abrogate the ability of large T antigen to transform mammalian cells. To examine whether a purified 136-amino-acid fragment from the T antigen amino terminus acts as a DnaJ-like chaperone, we investigated whether this fragment stimulates the ATPase activity of two hsc70s and discovered that ATP hydrolysis is stimulated four-to ninefold. In addition, ATPase-defective mutants of full-length T antigen, as well as wild-type small t antigen, stimulated the ATPase activity of hsc70. T antigen derivatives were also able to release an unfolded polypeptide substrate from an hsc70, an activity common to DnaJ chaperones. Because the J domain of T antigen plays essential roles in viral DNA replication, transcriptional control, virion assembly, and tumorigenesis, we conclude that this region may chaperone the rearrangement of multiprotein complexes.Simian virus 40 (SV40) encodes two proteins involved in tumorigenesis, the large and small tumor antigens. Large tumor antigen (T antigen) orchestrates many aspects of productive viral infection and is necessary and in many cases sufficient for tumorigenesis. T antigen is a 708-amino-acid multifunctional protein that elicits cellular transformation by acting on multiple targets, including members of the retinoblastoma tumor suppressor family (pRb, p107, and p130), members of the CBP family of transcriptional coactivators (CREB-binding protein [CBP], p300, and p400), and the tumor suppressor, p53. It is likely that additional T antigen targets important for transformation await discovery. T antigen sequences important for transformation map to two different regions of the molecule: the amino-terminal domain, which encompasses the first 125 amino acids, and a region located within the carboxyterminal half of the molecule (Fig. 1). Major questions that remain to be answered are the following. How does T antigen act on each of the cellular targets? How does the concerted action of T antigen on these multiple targets lead to tumorigenesis?Evidence that one or more independent transforming functions reside in the carboxy-terminal half o...

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SV40 Large T Antigen Functions at Two Distinct Steps in Virion Assembly

Cited by 35 publications

References 0 publications

T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis

T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis

The Minimum Replication Origin of Merkel Cell Polyomavirus Has a Unique Large T-Antigen Loading Architecture and Requires Small T-Antigen Expression for Optimal Replication

The Amino-Terminal Transforming Region of Simian Virus 40 Large T and Small t Antigens Functions as a J Domain

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