Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Minireviews
    • JVI Classic Spotlights
    • Archive
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About JVI
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Journal of Virology
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Minireviews
    • JVI Classic Spotlights
    • Archive
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About JVI
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Minireview

Polyomavirus T Antigens: Molecular Chaperones for Multiprotein Complexes

Jeffrey L. Brodsky, James M. Pipas
Jeffrey L. Brodsky
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James M. Pipas
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/JVI.72.7.5329-5334.1998
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Simian virus 40 (SV40) and murine polyomavirus (PyV) serve as powerful tools to identify key cellular regulatory proteins and to discern the mechanisms by which these proteins exert their biological effects. Like all members of the polyomavirus group, SV40 and PyV have simple genomes (Fig.1) that can be divided into an early region that is expressed prior to the onset of viral DNA replication and encodes the viral tumor antigens (T antigens) and a late region that encodes the viral capsid proteins (VP1, VP2, and VP3) (for a review, see reference 6). For the most part, SV40 and PyV co-opt cellular machines for viral DNA replication and transcription. In cell culture systems, the first 20 h postinfection is dedicated to driving the infected cells into the cell cycle so that cellular proteins needed for viral replication are expressed and in redirecting cell macromolecular synthesis systems to function in viral replication, transcription, and virion assembly. During this period the only viral proteins expressed are the T antigens, which play three critical roles in productive infection. The viral T antigens (i) alter and/or recruit specific host cell proteins to participate in virus production, (ii) block cellular antiviral defense systems, and (iii) participate directly in viral replication (e.g., large T antigens are DNA helicases and are thus required to replicate viral DNA).

Fig. 1.
  • Open in new tab
  • Download powerpoint
Fig. 1.

Genetic maps of SV40 and PyV. ori indicates position of the origin of DNA replication, PE is the early region promoter, PL is the late region promoter. Arrowed lines indicate coding sequences for viral proteins. Arrowhead indicates the carboxy terminus of the protein. LT, large T antigen; MT, middle T antigen; ST, small t antigen; and, TT, tiny t antigen.

In the polyomaviruses, all the T antigens are encoded by a common precursor mRNA that is differentially spliced to yield multiple monocistronic mature mRNAs. SV40 expresses three such mRNAs, one each for large T antigen, small t antigen, and tiny t antigen, whereas PyV expresses four mRNAs, one each for large, middle, small, and tiny T antigens (Fig. 2). The splicing pattern is such that all T antigens encoded by a given virus have a common amino-terminal domain. The large, middle, and small T antigens are multifunctional proteins that carry a diverse array of biochemical activities (6, 27). Some of these activities reside in discrete functional domains, while others require interdomain interaction and/or the independent action of two or more domains. In cell culture, only the large T antigen (SV40) or the large and middle T antigens (PyV) are essential for productive infection and viral tumorigenicity. The small t antigens, while not absolutely essential, contribute to both infection and transformation. Little is known about the tiny T antigens (36, 54).

Fig. 2.
  • Open in new tab
  • Download powerpoint
Fig. 2.

SV40 early region. Structure of the three early mRNAs is shown, along with a simplified domain map of the viral T antigens. Numbers above the line indicate SV40 genomic nucleotide position. Numbers below the line indicate amino acid position from the amino terminus of T antigen. Rb, retinoblastoma family-binding domain; p53, p53-binding region; pp2A, protein phosphatase 2A- binding domain.

T antigens mediate most of their biological effects by acting on specific cellular proteins (Table 1). For example, SV40 DNA replication requires the large T-antigen-mediated assembly of a preinitiation complex on the viral origin of replication (ori). T antigen binds ori directly through its DNA-binding domain, after which two T-antigen hexamers associate atori in an ATP-dependent reaction. T antigen then recruits cellular proteins such as DNA polymerase α, primase, topoisomerase, and RPA to the complex via direct physical associations. Following initiation, each of the hexamers functions in the elongation reaction as a DNA helicase. Transcription control, specifically transactivation of the viral capsid genes and of specific cellular genes, is also mediated by the interaction of large T antigen with cellular transcription factors (9, 18). Finally, the transforming functions of the large, middle, and small t antigens are mediated by their direct physical association with cellular target proteins. For example, large T antigens bind the retinoblastoma protein family of tumor suppressors (pRb, p107, and p130), PyV middle T antigen associates with a number of components of the cellular signal transduction network during transformation, and small t antigen contributes to transformation by acting on the cellular protein phosphatase pp2A (Table 1). Thus, successful infection requires the ordered assembly and rearrangement of several different multiprotein complexes involved in DNA replication, gene expression, and virion assembly. Although the mechanism(s) used by the T antigens to effect these diverse processes has been obscure, recent evidence from a number of laboratories indicates that a class of proteins known as molecular chaperones may coordinate many aspects of polyomavirus infection.

View this table:
  • View inline
  • View popup
Table 1.

Cellular proteins and protein complexes targeted by viral T antigensa

MOLECULAR CHAPERONES: ENGINEERS OF PROTEIN FUNCTION

Perhaps the best-studied molecular chaperones are the DnaK, DnaJ, and GrpE proteins, factors that were initially identified because mutations in the corresponding genes led to defects in phage λ replication (reviewed in reference 13). These chaperones possess unique activities, and homologs of each have been identified in all cell types from bacteria to humans.

DnaK is an ∼70-kDa ATPase whose synthesis is induced under heat shock or cellular stress conditions. Thus, proteins in the DnaK family are also known as Hsp70s (heat shock proteins with an apparent molecular weight of 70,000). DnaK is able to bind and release polypeptides concomitant with ATP binding and hydrolysis and possesses two distinct domains. The amino-terminal ∼44-kDa domain of DnaK is highly conserved among all DnaK family members, while the carboxyl ∼27-kDa domain is more variable and mediates substrate (i.e., polypeptide and possibly DnaJ) binding (10, 56).

The ATPase activity of DnaK is stimulated by DnaJ and GrpE. DnaJ is an ∼45-kDa molecular chaperone whose synthesis is also induced under stress conditions. DnaJ stimulates the rate-limiting hydrolysis of ATP of ADP on DnaK, thus locking polypeptide substrates into the chaperone (26). DnaJ family members have also been shown to bind directly some unfolded polypeptide substrates and folded proteins in order to exert specific chaperone-like activities (see below; reviewed in reference 16). The active interaction of DnaK and DnaJ chaperones is mediated by the J domain, a domain found in all DnaJ homologs, whose tertiary structure has been solved by nuclear magnetic resonance spectroscopy (17, 30, 34, 47). The J domain consists of four α-helices connected by loops and arranged such that helices 2 and 3 form a finger-like structure separated by the conserved sequence HPD (Fig. 3).

Fig. 3.
  • Open in new tab
  • Download powerpoint
Fig. 3.

Depiction of the SV40 T-antigen J domain. I, II, III, and IV indicate α-helices as determined by sequence comparisons and secondary structure predictions. Positions of mutations in SV40 mutants5110, dl1135, C6-1, C6-1R, and 5002 are shown. Although Spence and Pipas reported that5002 was a double amino acid substitution mutant (42), subsequent studies have determined that the defective phenotype is due solely to the L19F change.

GrpE is a nucleotide exchange factor that stimulates ADP/ATP exchange on DnaK. While DnaJ stimulates the steady-state ATPase activity of DnaK by about 10-fold, GrpE elicits only a 2-fold increase in DnaK’s ATPase activity; however, the combined action of both chaperones can yield a >50-fold increase in the ATPase activity of DnaK (22, 26).

DnaK, DnaJ, and GrpE form a potent molecular machine capable of modulating a variety of cellular processes. DnaK, DnaJ, and GrpE facilitate bacteriophage λ DNA replication by disassembling a protein complex at the origin of replication: the ATP-catalyzed release of the λP and DnaJ proteins activates the DnaB helicase, an event required for the initiation of DNA replication (1, 57). During bacteriophage P1 plasmid replication, DnaJ binds to the inactive, dimeric replication protein, RepA. The addition of DnaK, GrpE, and ATP to the DnaJ- RepA complex dissolves the RepA dimer, forming active RepA monomers (51). A direct interaction between these chaperones and the heat shock-specific ς32 transcription factor has also been observed (12). In addition, the DnaK, DnaJ, and GrpE proteins have been shown to facilitate protein folding, repair thermally damaged proteins, and prevent protein aggregation both in vivo and in vitro (11, 21, 39, 41). Because they can prevent protein aggregation and may act as proteinaceous machines, some chaperones are required to promote protein transport across biological membranes (2). Finally, mutations in the genes encoding DnaK, DnaJ, and GrpE lead to defects in the degradation of misfolded or mutant proteins (reviewed in reference 15). Together, these results indicate that molecular chaperones can monitor the conformations of proteins, retain polypeptides in solution, directly facilitate protein folding and transport, and alter the activities of enzyme complexes.

POLYOMAVIRUS T ANTIGENS CONTAIN ACTIVE DNAJ DOMAINS

Kelley and Landry (19) and Cheetham et al. (4) independently reported that the J domain and the common amino-terminal sequences of polyomavirus T antigens share sequence identities. The J-domain sequence HPD (amino acids 42 to 44) in SV40 large and small T antigens is conserved among the T antigens of all sequenced polyomaviruses (31). The predicted secondary structures of this region of the T antigens and known J domains are nearly identical, including the placement of the HPD motif in a loop between two α-helices (Fig. 3) (3, 40, 43). Because the interaction of DnaJ chaperones with their DnaK partners requires the J domain, it was not surprising to discover, in retrospect, that SV40 T antigen associates with the mammalian cytosolic DnaK homolog, hsc70, and that this association is mediated through the T-antigen amino terminus (37, 38). Consistent with the notion that this interaction is mediated by the J domain, mutations in the HPD sequence abolish the interaction of hsc70 with large T antigen (3).

Recently, a number of reports have firmly established the presence of a functional J domain at the amino terminus of polyomavirus T antigens. First, an amino-terminal fragment of SV40 T antigen that includes the J domain stimulates the ATPase activity of both hsc70 and a cytosolic yeast hsc70, Ssa1p (43). Full-length large and small T antigens also stimulate Ssa1p ATPase activity, and this stimulation is partially blocked by antibodies directed to the amino terminus of T antigen and by mutations within the J domain. Second, full-length T antigen and the amino-terminal fragment of T antigen facilitate the ATP-dependent release of an unfolded polypeptide bound to Ssa1p, another hallmark of a productive DnaJ-DnaK interaction (43). The tiny t antigen encoded by PyV also stimulates hsc70 ATPase activity (36). Third, Kelley and Georgopolous have shown that the J domain of SV40 inserted into the corresponding domain ofEscherichia coli DnaJ sustains bacterial growth and sensitivity to infection by bacteriophage λ (20); the J domains from the human polyomaviruses BK and JC also function in this system. Fourth, the J domain from the human HSJ-1 protein supports SV40 DNA replication when inserted into the corresponding region of T antigen (3, 45).

THE SV40 T ANTIGEN J DOMAIN IN VIRAL INFECTION AND TRANSFORMATION

Each polyomavirus T antigen has a J domain at the amino terminus, and in each case J-domain mutants are defective for some aspect of T-antigen function. Although T antigens with mutations in the J domain are frequently defective for DNA replication (29), it has proved difficult to identify the precise nature of the replication defect. This is because while J-domain mutants fail to replicate viral DNA in infected or transfected cells, the purified mutant T antigens exhibit all of the known biochemical activities necessary for replication and support various levels of SV40 DNA replication in vitro (7, 25, 50). Nonetheless, one replication-defective mutant,C6-1, contains two mutations (M30I and K51D) in the second and third helices of the J domain, respectively (Fig. 3) (14). Interestingly, a pseudorevertent of C6-1known as C6-1R contains a mutation in helix 3 that restores viability, suggesting that the three helices in the J domain cooperate to effect viral DNA replication. On the contrary, one inviable mutant (5002) with two alterations (L19F and P28S) in the J domain does replicate viral DNA but is defective at a late stage of virion assembly (42) and some mutations in helix 1 and in the loop between helices 1 and 2 have no effect on DNA replication. Furthermore, T antigens not only act with specific cellular proteins but oligomerize. Thus, a mutant missing the entire J domain (Δ1-82) showed a defect in oligomerization (50), whereas a small deletion within the J domain (dl1135) shows normal oligomerization (7).

A final difficulty in examining mutations in the T-antigen J domain is that the penetrance displayed by the mutants is variable. For example, in SV40 the D44N mutant is defective for viral DNA replication in vivo. However, this mutant transforms established cell lines with nearly wild-type frequency. On the other hand, an amino-terminal fragment of T antigen transforms several cell types and, in this context, the D44N mutant is transformation defective (43). Since the J domain mediates the interaction of T antigen with hsc70, one possible explanation for this effect is that hsc70 binds T antigen through sequences near the carboxy terminus of T antigen in addition to the J domain. In this scenario, D44N in the full-length protein might bind a critical amount of hsc70 to function, whereas binding is defective in the absence of the carboxy terminus.

In-frame deletion mutants within the large T/small t common domain of SV40 T antigen are defective for the transformation of established cell lines (8, 32, 43, 55). Srinivasan et al. (43) reported that mutations in either the SV40 J domain or the T-antigen/Rb interaction motif (LXCXE motif) are transformation defective. Furthermore, these sequences must be in cis. This suggests that the J domain itself, or some cellular protein recruited by the J domain, such as hsc70, must act on the bound Rb to elicit transformation, a result consistent with reports that both the J domain and Rb-binding domains must be functional for T antigen to mediate increased degradation of p107 and p130 (45). More recently it has been shown that in SV40 and PyV, both the J domain and Rb-binding motifs are required to inactivate the tumor-suppressing functions of the Rb family (40, 44, 53).

The role of the SV40 J domain has also been examined in transgenic mice and further demonstrates that the J- and Rb-binding domains act incis. When driven by the lymphotropic polyomavirus promoter, wild-type T antigen induces rapid tumorigenesis of the choroid plexus (5) but mutations in either the J domain (dl1135) or the Rb-binding domain (K1) prevent choroid plexus tumorigenesis (46). Furthermore, transgenic animals expressing both 1135 and K1 do not get tumors (49).

The J domain must also act in cis with some transforming function that maps to the carboxy-terminal half of T antigen (43). One possibility is that J-domain function is required for T antigen to block p53 tumor suppression functions. This would be consistent with the observations that (i) p53 binds to the carboxy-terminal half of T antigen, and (ii) a J domain mutant (dl1135) fails to block p53-mediated growth arrest (35). Another candidate for this transforming function is the CBP family of transcriptional adapter proteins (CBP, p300, and p400) (23). Transformation by the adenovirus E1A protein is mediated in part by E1A binding to this protein family. Transformation-defective mutants of E1A that fail to bind p300 are rescued by SV40 T antigen, and dl1135 is defective for this rescue (50), indicating that the J domain is required for the action of T antigen on the CBP family.

In contrast to the data presented above, there are two instances in which the J domain is not needed for some aspect of transformation. First, a T-antigen J-domain mutant (1135) is able to induce T-cell lymphomas in transgenic mice even though this same mutant is defective for tumorigenesis in other tissues such as the choroid plexus or B cells (46). Second, the T-antigen J domain is not essential to immortalize C57BL/6 mouse embryo fibroblasts (48). These results reemphasize that the penetrance displayed in vivo by J-domain mutants is variable.

T ANTIGENS TARGET MULTIPROTEIN COMPLEXES FOR CHAPERONE ACTION

The bacteriophage λ offers a paradigm as to how molecular chaperones might function in polyomavirus infection. During infection, λ DnaJ and DnaK free the DnaB helicase from its stable association with the multiprotein preinitiation complex at the viral origin of DNA replication. The energy needed to dissolve this association is provided by DnaK-mediated ATP hydrolysis and is used to alter the conformation of one or more members of the complex. However, there are important distinctions between λ and the polyomaviruses. First, the polyomaviruses encode their own DnaJ chaperones, the T antigens, and use them to recruit both hsc70 and the target cellular protein complexes. Second, the polyomaviruses use their chaperone machine for viral functions in addition to DNA replication, i.e., transcriptional control and virion assembly. However, one common theme that connects the disparate functions displayed by λ and polyomaviruses is the ensuing rearrangement of multiprotein complexes.

The fact that the J domain must act in cis with the Rb- and p53-binding domains to elicit transformation suggests a novel mechanism for T-antigen/chaperone action on tumor suppressors. The current model states that T antigen blocks tumor suppressor function by sequestering Rb proteins and p53 into stable, inactive complexes. The fact that chaperone action is needed in concert with the tumor suppressor-binding functions of T antigen suggests a more dynamic model (Fig.4). In this model, T antigen recruits a target protein or protein complex into a ternary complex consisting of the target, T antigen, and hsc70. Energy, derived from ATP hydrolysis by hsc70, is then used to effect a conformational change on one or more components of the target complex, as occurs during λ DNA replication. For example, this energy might be used to release one or more proteins from an Rb-E2F complex to allow the E2F-dependent transcription of cellular genes that are required for viral replication.

Fig. 4.
  • Open in new tab
  • Download powerpoint
Fig. 4.

Model for T-antigen chaperone action on a multiprotein complex. First, T antigen recruits ATP-bound hsc70 via the J domain and the target protein complex via a substrate-binding domain into an activated complex (asterisk). Next, energy derived from hsc70-mediated ATP hydrolysis induces a conformational change in one or more members of the target complex. This is followed by release of hsc70 and the altered target that can now act as an effector for downstream signaling events. II, III, and IV, J-domain α-helices.

Similarly, the rearrangement of large multiprotein complexes is a common feature of many cellular processes, including signal transduction, DNA replication, and transcriptional regulation, all of which are targets of T-antigen action (Table 1). Perhaps the T antigens act, in part, as scaffolds to recruit specific members of these complexes to associate with the chaperones. The chaperone machine would then be positioned to orchestrate the energy-dependent rearrangement of the multiprotein complex (Fig. 4).

FUTURE DIRECTIONS

Thus far, hsc70 is the only DnaK homolog found to associate with the T-antigen J domain. This does not exclude the possibility that known or new members of this family might be needed for viral infection, especially considering that mammals encode many DnaK and DnaJ homologs. For example, the incomplete penetrance of the SV40 D44N mutation (see above) might be due to the differential effects of this mutation on the interaction of T antigen with different DnaK homologs, one required for replication and another needed for transformation.

While it is clear that the action of T antigen on the Rb family requires a cis-acting J domain, there is one case in which a J-domain function can be supplied in trans. Small t antigen has been shown to transactivate the cyclin A gene, and transcriptional activation is blocked by mutations in the J domain (33). However, transcriptional activation is restored when a wild-type J domain is supplied in trans. Clearly we must decipher why some T-antigen chaperone functions must act in cis, while others may be supplied in trans.

The human papillomaviruses (HPV) and adenoviruses also encode transforming proteins that act on the Rb family and p53 tumor suppressors, but none of these proteins (E7, E6, E1A, or E1B 55K) possesses a J domain. If chaperone action is required for the modulation of tumor suppressor function, how do these proteins act? One intriguing possibility is that they may bind and recruit cellular DnaJ proteins, a hypothesis supported by the observation that the HPV18 E7 protein binds a human DnaJ homolog (28). Similarly, the replication of HPV11 DNA in vitro is greatly enhanced by the addition of exogenous hsp40 and hsc70, suggesting a role for chaperones in HPV replication (24).

While this research is in its infancy, it is already clear that molecular chaperones play a vital role in polyomavirus infection. Since work with polyomaviruses has shown that chaperone action is needed for several fundamental biological processes, i.e., DNA replication, transcription, and virion assembly, we suggest that many, if not all, viruses will either encode chaperones or recruit cellular chaperones. Such a hypothesis is readily testable and is already being investigated in numerous laboratories.

ACKNOWLEDGMENTS

This work was supported by grant CA40586 from the NIH to J.M.P. and by grant MCB9506002 from the NSF and a Junior Faculty Research Award from the American Cancer Society to J.L.B.

We thank Alison Slinskey and Jim Tremblay for help with the figures. We also thank Jim DeCaprio, Karl Munger, Terry Van Dyke, Tom Broker, and Louise Chow for allowing us to cite their unpublished observations.

  • Copyright © 1998 American Society for Microbiology

REFERENCES

  1. 1.↵
    1. Alfano C.,
    2. McMacken R.
    Heat shock protein-mediated disassembly of nucleoprotein structures is required for the initiation of bacteriophage λ replication.J. Biol. Chem. 264 1989 10709 10718
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Brodsky J. L.
    Post-translational protein translocation: not all Hsp70s are created equal.Trends Biochem. Sci. 21 1996 121 126
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Campbell K. S.,
    2. Mullane K. P.,
    3. Aksoy I. A.,
    4. Stubdal H.,
    5. Zalvide J.,
    6. Pipas J. M.,
    7. Silver P. A.,
    8. Roberts T. M.,
    9. Schaffhausen B. S.,
    10. DeCaprio J. A.
    DnaJ/hsp40 chaperone domain of SV40 large T antigen promotes efficient viral DNA replication.Genes Dev. 11 1997 1098 1110
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Cheetham M. E.,
    2. Brion J. P.,
    3. Anderton B. H.
    Human homologues of the bacterial heat-shock protein DnaJ are preferentially expressed in neurons.Biochem. J. 284 1992 469 476
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Chen J.,
    2. Tobin G. J.,
    3. Pipas J. M.,
    4. Van Dyke T.
    T antigen mutant activities in vivo: roles of p53 and pRB binding in tumorigenesis of the choroid plexus.Oncogene 7 1992 1167 1175
    OpenUrlPubMedWeb of Science
  6. 6.↵
    1. Cole C. N.
    Polyomavirinae: the viruses and their replication Virology 3rd ed. Fields B., et al. 1996 1997 2026 Lippincott-Raven New York, N.Y
  7. 7.↵
    1. Collins B. S.,
    2. Pipas J. M.
    T antigens encoded by replication-defective SV40 mutants dl1135 and 5080.J. Biol. Chem. 270 1995 15377 15384
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Conzen S. D.,
    2. Cole C. N.
    The three transforming regions of SV40 T antigen are required for immortalization of primary mouse embryo fibroblasts.Oncogene 11 1995 2295 2302
    OpenUrlPubMedWeb of Science
  9. 9.↵
    1. Damania B.,
    2. Alwine J. C.
    TAF-like function of SV40 large T antigen.Genes Dev. 10 1996 1369 1381
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Flaherty K. M.,
    2. DeLuca-Flaherty C.,
    3. McKay D. B.
    Three dimensional structure of the ATPase fragment of a 70K heat shock cognate protein.Nature 346 1990 623 628
    OpenUrlCrossRefPubMedWeb of Science
  11. 11.↵
    1. Gaitanaris G. A.,
    2. Papavassiliou A. G.,
    3. Rubock P.,
    4. Silverstein S. J.,
    5. Gottesman M. E.
    Renaturation of denatured λ repressor requires heat shock proteins.Cell 61 1990 1013 1020
    OpenUrlCrossRefPubMedWeb of Science
  12. 12.↵
    1. Gamer J.,
    2. Bujard H.,
    3. Bukau B.
    Physical interaction between heat shock proteins DnaK, DnaJ, and GrpE and the bacterial heat shock transcription factor ς32.Cell 69 1992 833 842
    OpenUrlCrossRefPubMedWeb of Science
  13. 13.↵
    1. Georgopoulos C.,
    2. Liberek K.,
    3. Zylicz M.,
    4. Ang D.
    Properties of the heat shock proteins of Escherichia coli and the autoregulation of the heat shock response The biology of heat shock proteins and molecular chaperones. Morimoto R. I., Tessieres A., Georgopoulos C. 1994 209 249 Cold Spring Harbor Laboratory Press Cold Spring Harbor, N.Y
  14. 14.↵
    1. Gluzman Y.,
    2. Ahrens B.
    SV40 early mutants that are defective for viral DNA synthesis but competent for transformation of cultured rat and simian cells.Virology 22 1982 78 92
    OpenUrl
  15. 15.↵
    1. Gottesman S.,
    2. Wickner S.,
    3. Maurizi M. R.
    Protein quality control: triage by chaperones and proteases.Genes Dev. 11 1997 815 823
    OpenUrlFREE Full Text
  16. 16.↵
    1. Hartl F. U.
    Molecular chaperones in cellular protein folding.Nature 381 1996 571 580
    OpenUrlCrossRefPubMedWeb of Science
  17. 17.↵
    1. Hill R. B.,
    2. Flanagan J. M.,
    3. Prestegard J. H.
    1H and 15N magnetic resonance assignments, secondary structure, and tertiary fold of Escherichia coli DnaJ(1–78).Biochemistry 34 1995 5587 5596
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Johnston S. D.,
    2. Yu X. M.,
    3. Mertz J. E.
    The major transcriptional transactivation domain of simian virus 40 large T antigen associates nonconcurrently with multiple components of the transcriptional preinitiation complex.J. Virol. 70 1996 1191 1202
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Kelley W. L.,
    2. Landry S. J.
    Chaperone power in a virus? Trends Biochem. Sci. 19 1994 277 278
    OpenUrlCrossRefPubMedWeb of Science
  20. 20.↵
    1. Kelley W. L.,
    2. Georgopolous C.
    The T/t common exon of SV40, JCV, and BK polyomavirus T antigens can functionally replace the J-domain of the Escherichia coli DnaJ molecular chaperone.Proc. Natl. Acad. Sci. USA 94 1997 3679 3684
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Langer T.,
    2. Lu C.,
    3. Echols H.,
    4. Flanagan J.,
    5. Hayer M. K.,
    6. Hartl F. U.
    Successive action of dnaK, dnaJ and GroEL along the pathway of chaperone-mediated folding.Nature 356 1992 683 689
    OpenUrlCrossRefPubMedWeb of Science
  22. 22.↵
    1. Liberek K.,
    2. Marszalek J.,
    3. Ang D.,
    4. Georgopoulos C.,
    5. Zylicz M.
    Escherichia coli dnaJ and grpE heat shock proteins jointly stimulate ATPase activity of dnaK.Proc. Natl. Acad. Sci. USA 88 1991 2874 2878
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Lill N. I.,
    2. Tevethia M. J.,
    3. Eckner R.,
    4. Livingston D. M.,
    5. Modjtahedi N.
    p300 family members associate with the carboxy terminus of simian virus 40 large tumor antigen.J. Virol. 71 1997 129 137
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    Liu, J.-S., S.-R. Kuo, D. M. Cyr, T. R. Broker, and L. T. Chow. Personal communication.
  25. 25.↵
    1. Maulbecker C.,
    2. Mohr I.,
    3. Gluzman Y.,
    4. Bartholomew J.,
    5. Botchan M.
    A deletion in the simian virus 40 large T antigen impairs lytic replication in monkey cells in vivo but enhances DNA replication in vitro: new complementation function of T antigen.J. Virol. 66 1992 2195 2207
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. McCarty J. S.,
    2. Buchberger A.,
    3. Reinstein J.,
    4. Bukau B.
    The role of ATP in the functional cycle of the DnaK chaperone system.J. Mol. Biol. 249 1995 126 137
    OpenUrlCrossRefPubMedWeb of Science
  27. 27.↵
    1. Messerschmitt A. S.,
    2. Dunant N.,
    3. Ballmer-Hofer K.
    DNA tumor viruses and src family tyrosine kinases, an intimate relationship.Virology 227 1997 271 280
    OpenUrlCrossRefPubMedWeb of Science
  28. 28.↵
    Munger, K. Personal communication.
  29. 29.↵
    1. Peden K. W. C.,
    2. Pipas J. M.
    Simian virus 40 mutants with amino-acid substitutions near the amino-terminus of large T antigen.Virus Genes 6 1992 107 118
    OpenUrlCrossRefPubMedWeb of Science
  30. 30.↵
    1. Pellecchia M.,
    2. Szyperski T.,
    3. Wall D.,
    4. Georgopolous C.,
    5. Wüthrich K.
    NMR structure of the J-domain and the Gly/Phe-rich region of the Escherichia coli DnaJ chaperone.J. Mol. Biol. 260 1996 236 250
    OpenUrlCrossRefPubMedWeb of Science
  31. 31.↵
    1. Pipas J. M.
    Common and unique features of T antigens encoded by the polyomavirus group.J. Virol. 66 1992 3979 3985
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Pipas J. M.,
    2. Peden K. W. C.,
    3. Nathans D.
    Mutational analysis of simian virus 40 T antigen: isolation and characterization of mutants with deletions in the T-antigen gene.Mol. Cell. Biol. 3 1983 203 213
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Porras A.,
    2. Bennett J.,
    3. Howe A.,
    4. Tokos K.,
    5. Bouck N.,
    6. Henglein B.,
    7. Sathyamangalam S.,
    8. Thimmapaya B.,
    9. Rundell K.
    A novel simian virus 40 early-region domain mediates transactivation of the cyclin A promoter by small-t antigen and is required for transformation in small-t antigen-dependent assays.J. Virol. 70 1996 6902 6908
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Qian Y. Q.,
    2. Patel D.,
    3. Hartl F.-U.,
    4. McColl D. J.
    Nuclear magnetic resonance solution structure of the human Hsp40 (HDJ-1) J-domain.J. Mol. Biol. 260 1996 224 235
    OpenUrlCrossRefPubMedWeb of Science
  35. 35.↵
    1. Quartin R. S.,
    2. Cole C. N.,
    3. Pipas J. M.,
    4. Levine A. J.
    The amino-terminal functions of the simian virus 40 large T-antigen are required to overcome wild-type p53-mediated growth arrest of cells.J. Virol. 68 1994 1334 1341
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Riley M. I.,
    2. Yoo W.,
    3. Mda N. Y.,
    4. Folk W. R.
    Tiny T antigen: an autonomous polyomavirus T antigen amino-terminal domain.J. Virol. 71 1997 6068 6074
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Sawai E. T.,
    2. Butel J. S.
    Association of a cellular heat shock protein with simian virus 40 large T antigen in transformed cells.J. Virol. 63 1989 3961 3973
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Sawai E. T.,
    2. Rasmussen G.,
    3. Butel J. S.
    Construction of SV40 deletion mutants and delimitation of the binding domain for heat shock protein to the amino terminus of large T-antigen.Virus Res. 31 1994 367 378
    OpenUrlCrossRefPubMedWeb of Science
  39. 39.↵
    1. Schröder H.,
    2. Langer T.,
    3. Hartl F.-U.,
    4. Bukau B.
    DnaK, DnaJ, and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage.EMBO J. 12 1993 4137 4144
    OpenUrlCrossRefPubMedWeb of Science
  40. 40.↵
    1. Sheng Q.,
    2. Denis D.,
    3. Ratnofsky M.,
    4. Roberts T. M.,
    5. DeCaprio J. A.,
    6. Schaffhausen B.
    The DnaJ domain of polyomavirus large T antigen is required to regulate Rb family tumor suppressor function.J. Virol. 71 1997 9410 9416
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Skowyra D.,
    2. Georgopoulos C.,
    3. Zylicz M.
    The E. coli dnaK gene product, the hsp70 homolog, can reactivate heat-inactivated RNA polymerase in an ATP hydrolysis-dependent manner.Cell 62 1990 939 944
    OpenUrlCrossRefPubMedWeb of Science
  42. 42.↵
    1. Spence S. L.,
    2. Pipas J. M.
    SV40 large T antigen functions at two distinct steps in viron assembly.Virology 204 1994 200 209
    OpenUrlCrossRefPubMedWeb of Science
  43. 43.↵
    1. Srinivasan A.,
    2. McClellan A. J.,
    3. Vartikar J.,
    4. Marks I.,
    5. Cantalupo P.,
    6. Li Y.,
    7. Whyte P.,
    8. Rundell K.,
    9. Brodsky J. L.,
    10. Pipas J. M.
    The amino-terminal transforming region of simian virus 40 large and small T antigens function as a J-domain.Mol. Cell. Biol. 17 1997 4761 4773
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    1. Stubdal H.,
    2. Zalvide J.,
    3. Campbell K. S.,
    4. Schweitzer C.,
    5. Roberts T. M.,
    6. DeCaprio J. A.
    Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen.Mol. Cell. Biol. 17 1997 4979 4990
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Stubdal H.,
    2. Zalvide J.,
    3. DeCaprio J. A.
    Simian virus 40 large T antigen alters the phosphorylation state of the RB-related proteins p130 and p107.J. Virol. 70 1996 2781 2788
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Symonds H. S.,
    2. McCarthy S. A.,
    3. Chen J.,
    4. Pipas J. M.,
    5. Van Dyke T.
    Use of transgenic mice reveals cell-specific transformation by a simian virus 40 T-antigen amino-terminal mutant.Mol. Cell. Biol. 13 1993 3255 3265
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Szyperski T.,
    2. Pellecchia M.,
    3. Wall D.,
    4. Georgopolous C.,
    5. Wüthrich K.
    NMR structure determination of the Escherichia coli DnaJ molecular chaperone: secondary structure and backbone fold of the N-terminal region (residues 2-108) containing the highly conserved J domain.Proc. Natl. Acad. Sci. USA 91 1994 11343 11347
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Tevethia M. J.,
    2. Lacko H. A.,
    3. Kierstead T. D.,
    4. Thompson D. L.
    Adding an Rb-binding site to an N-terminally truncated simian virus 40 T antigen restores growth to high cell density, and the T common region in trans provides anchorage-independent growth and rapid growth in low serum concentrations.J. Virol. 71 1997 1888 1896
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    Van Dyke, T. Personal communication.
  50. 50.↵
    1. Weisshart K.,
    2. Bradley M. K.,
    3. Weiner B. M.,
    4. Schneider C.,
    5. Moarefi I.,
    6. Fanning E.,
    7. Arthur A. K.
    An N-terminal deletion mutant of simian virus (SV40) large T antigen oligomerizes incorrectly on SV40 DNA but retains the ability to bind to DNA polymerase alpha and replicate SV40 DNA in vitro.J. Virol. 70 1996 3509 3516
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Wickner S.,
    2. Hoskins J.,
    3. McKenney K.
    Function of DnaJ and DnaK as chaperones in origin-specific DNA binding by RepA.Nature 350 1991 165 167
    OpenUrlCrossRefPubMedWeb of Science
  52. 52.
    1. Yaciuk P.,
    2. Carter M. C.,
    3. Pipas J. M.,
    4. Moran E.
    Simian virus 40 large T antigen expresses a biological activity complementary to the p300-associated transforming function of the adenovirus E1A gene products.Mol. Cell. Biol. 11 1991 2116 2124
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Zalvide J.,
    2. Stubdal H.,
    3. DeCaprio J. A.
    The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins.Mol. Cell. Biol. 18 1998 1408 1415
    OpenUrlAbstract/FREE Full Text
  54. 54.↵
    1. Zerrahn J.,
    2. Knippschild U.,
    3. Winkler T.,
    4. Deppert W.
    Independent expression of the transforming amino-terminal domain of SV40 large T antigen from an alternatively spliced third SV40 early mRNA.EMBO J. 12 1993 4739 4746
    OpenUrlPubMedWeb of Science
  55. 55.↵
    1. Zhu J.,
    2. Rice P. W.,
    3. Gorsch L.,
    4. Abate M.,
    5. Cole C. N.
    Transformation of a continuous rat embryo fibroblast cell line requires three separate domains of simian virus 40 large T antigen.J. Virol. 66 1992 2780 2791
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Zhu X.,
    2. Zhao X.,
    3. Burkholder W. F.,
    4. Gragerov A.,
    5. Ogata C. M.,
    6. Gottesman M. E.,
    7. Hendrickson W. A.
    Structural analysis of substrate binding by the molecular chaperone DnaK.Science 272 1996 1606 1614
    OpenUrlAbstract
  57. 57.↵
    1. Zylicz M.,
    2. Ang D.,
    3. Liberek K.,
    4. Georgopoulos C.
    Initiation of λ DNA replication with purified host and bacteriophage encoded proteins: the role of the dnaK, dnaJ, and grpE heat shock proteins.EMBO J. 8 1989 1601 1608
    OpenUrlPubMedWeb of Science
PreviousNext
Back to top
Download PDF
Citation Tools
Polyomavirus T Antigens: Molecular Chaperones for Multiprotein Complexes
Jeffrey L. Brodsky, James M. Pipas
Journal of Virology Jul 1998, 72 (7) 5329-5334; DOI: 10.1128/JVI.72.7.5329-5334.1998

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Journal of Virology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Polyomavirus T Antigens: Molecular Chaperones for Multiprotein Complexes
(Your Name) has forwarded a page to you from Journal of Virology
(Your Name) thought you would be interested in this article in Journal of Virology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Polyomavirus T Antigens: Molecular Chaperones for Multiprotein Complexes
Jeffrey L. Brodsky, James M. Pipas
Journal of Virology Jul 1998, 72 (7) 5329-5334; DOI: 10.1128/JVI.72.7.5329-5334.1998
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • MOLECULAR CHAPERONES: ENGINEERS OF PROTEIN FUNCTION
    • POLYOMAVIRUS T ANTIGENS CONTAIN ACTIVE DNAJ DOMAINS
    • THE SV40 T ANTIGEN J DOMAIN IN VIRAL INFECTION AND TRANSFORMATION
    • T ANTIGENS TARGET MULTIPROTEIN COMPLEXES FOR CHAPERONE ACTION
    • FUTURE DIRECTIONS
    • ACKNOWLEDGMENTS
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Antigens, Polyomavirus Transforming
Molecular Chaperones

Related Articles

Cited By...

About

  • About JVI
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #Jvirology

@ASMicrobiology

       

 

JVI in collaboration with

American Society for Virology

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0022-538X; Online ISSN: 1098-5514