Mechanisms of cell transformation induced by polyomavirus

Oliveira, Maria Leonor S.; Brochado, Sheila Maria; Sogayar, Mari Cleide

doi:10.1590/s0100-879x1999000700010

Cited by 7 publications

(8 citation statements)

References 39 publications

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“…Middle T antigen is not encoded by SV40 but is made by a subset of the polyomaviruses including polyomavirus itself. Middle T antigen is a transforming protein that activates cytoplasmic signal transduction proteins (168). Mutations in the middle-T-antigen J domain render it defective for inducing transformation (44).…”

Section: Role Of the J Domain In Other T Antigensmentioning

confidence: 99%

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

Sullivan

Pipas

2002

Microbiol Mol Biol Rev

222

227

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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: Role Of the J Domain In Other T Antigensmentioning

confidence: 99%

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

Sullivan

Pipas

2002

Microbiol Mol Biol Rev

222

227

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“…In contrast to SV40, Py encodes a middle T antigen that is essential for it to transform cultured cells or cause tumors in mice (28,49). Indeed, middle T alone is sufficient to transform established cell lines, although the immortalizing function of large T is also required for transforming primary fibroblasts (43,44,50).…”

Section: Middle T Antigen Contributes To the Activation Of Pol III Trmentioning

confidence: 99%

“…This oncoprotein can therefore serve as a very potent inducer of pol III transcription in vivo, despite the fact that it is situated at membranes outside of the nucleus (51,52). Its ability to achieve this activation is likely to result from its well documented capacity to stimulate a variety of signal transduction pathways (49,53). This possibility is supported by the failure of NG59 to increase VA1 expression, because this substitution mutant (Asp-179 replaced by Ile-Asn) is unable to activate the signaling cascades that respond to wild-type middle T (32).…”

Section: Middle T Antigen Contributes To the Activation Of Pol III Trmentioning

confidence: 99%

“…Middle T is generated by alternative splicing of the viral early transcript and has no equivalent in SV40 (54). Nevertheless, it is the principal oncoprotein of Py, being sufficient to transform immortalized cells (28,43,44,49,50). It achieves this through association with signal transducers, such as members of the Src family, phosphatidylinositol 3-kinase, and the SHC protein that activates the Ras pathway (see Refs.…”

Section: Middle T Antigen Contributes To the Activation Of Pol III Trmentioning

confidence: 99%

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Multiple Mechanisms Contribute to the Activation of RNA Polymerase III Transcription in Cells Transformed by Papovaviruses

Felton-Edkins¹,

White

2002

Journal of Biological Chemistry

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RNA polymerase (pol) III transcription is abnormally active in fibroblasts transformed by polyomavirus (Py) or simian virus 40 (SV40). Several distinct mechanisms contribute to this effect. In untransformed fibroblasts, the basal pol III transcription factor (TF) IIIB is repressed through association with the retinoblastoma protein RB; this restraint is overcome by large T antigens of Py and SV40. Furthermore, cells transformed by these papovaviruses overexpress the BDP1 subunit of TFIIIB, at both the protein and mRNA levels. Despite the overexpression of BDP1, the abundance of the other TFIIIB components is unperturbed following papovavirus transformation. In contrast, mRNAs encoding all five subunits of the basal factor TFIIIC2 are found at elevated levels in fibroblasts transformed by Py or SV40. Thus, both papovaviruses stimulate pol III transcription by boosting production of selected components of the basal machinery. Py differs from SV40 in encoding a highly oncogenic middle T antigen that localizes outside the nucleus and activates several signal transduction pathways. Middle T can serve as a potent activator of a pol III reporter in transfected cells. Several distinct mechanisms therefore contribute to the high levels of pol III transcription that accompany transformation by Py and SV40. RNA polymerase (pol)1 III synthesizes many essential products, including tRNA, 5S rRNA, 7SL RNA, and U6 snRNA (1). Pol III products are overexpressed in a wide variety of cell lines transformed by DNA tumor viruses, RNA tumor viruses, or chemical carcinogens (e.g. Refs. 2-6). These observations also apply to rodent and human tumors in vivo (7-9). For example, RT-PCR assays showed that tRNA, 5S rRNA, and 7SL RNA are overproduced consistently in human ovarian cancers (9). An extensive Northern analysis of 80 tumor specimens representing 19 types of cancer revealed that 7SL RNA is abnormally abundant in every tumor analyzed, relative to healthy tissue from the same patient (8). Furthermore, in situ hybridization of breast, lung, and tongue carcinomas showed increased levels of pol III transcripts in neoplastic cells relative to the surrounding healthy tissue (7,8).The first indication that pol III responds to cell transformation came from studies with murine fibroblasts transformed by simian virus 40 (SV40) (2, 3, 10). When different SV40-transformed clones are compared, the highest abundance of pol III transcripts is found in those that most efficiently induce tumors, whereas lower levels are detected in the less tumorigenic lines (2, 4). A tight link between transformation and pol III induction is suggested by lines transformed using temperaturesensitive mutants of the SV40 oncoprotein large T antigen; these activate pol III transcription within 30 min of transfer to the permissive temperature (11) and rapidly down-regulate pol III products when returned to nonpermissive conditions, while reverting to normal morphology and phenotype (2). SV40 large T antigen has also been shown to activate pol III transcription in vitro ...

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“…The MT phosphoprotein associates with the cell membrane and does not appear to display any enzymatic activity of its own. Instead, it exerts its effects in the host cell by interacting with, and altering the activities of essential growth regulatory proteins that have been implicated in normal cell growth control [Pallas et al, 1988; Armelin and Oliveira, 1996; Oliveira et al, 1999; Ichaso and Dilworth, 2001; Dilworth, 2002]. Examples of cellular proteins that bind to MT are: pp60 c‐src , c‐ yes , and c‐ fyn kinases [Courtneidge and Smith, 1983; Kornbluth et al, 1986; Kaplan et al, 1987; Horak et al, 1989; Su et al, 1995; Dunant et al, 1996], phosphatidylinositol 3‐kinase (PI3K) [Whitman et al, 1985], protein phosphatase 2A [Glenn and Eckhart, 1993; Campbell et al, 1995], Shc [Campbell et al, 1994; Dilworth et al, 1994; Blaikie et al, 1997], phospholipase Cγ (PLCγ) [Su et al, 1995], and 14‐3‐3 [Pallas et al, 1994; Culleré et al, 1998].…”

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confidence: 99%

Suppression of AP‐1 constitutive activity interferes with polyomavirus MT antigen transformation ability

Winnischofer¹,

Oliveira²,

Sogayar³

2003

J of Cellular Biochemistry

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Polyomavirus (Py) encodes a potent oncogene, the middle T antigen (MT), that induces cell transformation by binding to and activating several cytoplasmic proteins which take part in transduction of growth factors-induced mitogenic signal to the nucleus. We have previously reported that the AP-1 transcriptional complex is a target for MT during cell transformation although, its activation was not sufficient for establishment of the transformed phenotype. Here we show that expression of a dominant-negative cJun mutant in MT transformed cell lines inhibits its transformation ability, indicating that constitutive AP-1 activity is necessary for cell transformation mediated by MT. Evidences also suggest that proliferation of MT transformed cells in low serum concentrations and their ability to form colonies in agarose are controlled by distinct mechanisms.

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Mechanisms of cell transformation induced by polyomavirus

Cited by 7 publications

References 39 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

Multiple Mechanisms Contribute to the Activation of RNA Polymerase III Transcription in Cells Transformed by Papovaviruses

Suppression of AP‐1 constitutive activity interferes with polyomavirus MT antigen transformation ability

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