Independent expression of the transforming amino-terminal domain of SV40 large I antigen from an alternatively spliced third SV40 early mRNA.

Zerrahn, Jens; Knippschild, Uwe; Winkler, Thomas; Deppert, Wolfgang

doi:10.1002/j.1460-2075.1993.tb06162.x

Cited by 92 publications

(86 citation statements)

References 55 publications

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“…1). This splicing pattern can be detected in MCC tumors by PCR with primers flanking the splicing junction and may represent transcripts for alternatively spliced analogues to SV40 17kT transcript (14). No transcript corresponding to the MuPyV MT antigen was found but we cannot rule out low abundance transcription that was not detected.…”

Section: Resultsmentioning

confidence: 82%

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Shuda

Feng

Kwun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

639

908

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Merkel cell polyomavirus (MCV) is a virus discovered in our laboMerkel cell carcinoma ͉ pRB interaction ͉ viral integration ͉ virus replication ͉ helicase M erkel cell carcinoma (MCC) is an aggressive skin cancer associated with sun exposure and immunosuppression (1, 2). Using digital transcriptome subtraction, we recently identified Merkel cell polyomavirus (MCV) as a novel polyomavirus integrated into the genome of MCC tumors (3, 4). The close association between MCV and MCC has been confirmed by others (5). Polyomaviruses are small circular DNA viruses encoding a T antigen oncoprotein locus. T antigens are expressed from variably spliced viral transcripts that target tumor suppressor and cell cycle regulatory proteins, including retinoblastoma tumor suppressor protein (Rb) (6), p53 (7, 8), protein phosphatase 2A (9), and Bub1 (10). Murine polyomavirus (MuPyV) middle T (MT) antigen, a membrane-bound protein, is particularly potent in initiating cell transformation through interactions with phosphatidylinositol 3-kinase, protein phosphatase 2A, Src, and Shc proteins (11,12). MCV large T (LT) antigen retains conserved domains, such as pocket Rb binding LXCXE and DnaJ motifs, present across virus species (13). LT not only encodes tumor suppressor targeting domains but also origin binding and helicase/ATPase functions required for viral genome replication. MCV integration in MCC tumors is incompatible with transmissible virus and likely represents a rare biological accident in which the tumor cell is a dead-end host. The monoclonal pattern of MCV integration into MCC tumors suggests that virus integration occurs before tumor cell expansion and that MCV is a contributing factor in a portion of MCC (3).We have isolated MCV T antigen sequences from both tumor cases and nontumor cases to characterize their abilities to act as a viral DNA replicase. Sequence analysis demonstrates that LT protein is prematurely truncated in all MCC cases, whereas the Rb-interacting domain is preserved. Viruses from nontumor sources do not possess these mutations. We also describe here an MCC cell line stably harboring MCV and an origin replication assay to assess MCV replication. We show that wild type (WT) LT from nontumorous sources activates MCV replication of integrated tumor virus, suggesting that MCV-associated MCC arises from a two-step process in which viral genome integrates into the host genome and develops T antigen mutations to prevent autonomous viral genome replication. Failure to truncate the viral T antigen may lead to DNA damage responses or immune recognition that hinders nascent tumor cell survival.

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Section: Resultsmentioning

confidence: 82%

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Shuda

Feng

Kwun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

639

908

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“…The SV40 early region encodes three proteins through alternative splicing, the large T (LT), small T (ST) and 17 kT antigens (Shenk et al, 1976;Sleigh et al, 1978;Khalili et al, 1987;Zerrahn et al, 1993). Among these three early proteins, LT and ST have been intensively studied because they not only have important roles in viral transcription and replication but also participate in cell immortalization and transformation (Ali and DeCaprio, 2001;Rundell and Parakati, 2001).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

Wang

et al. 2011

Oncogene

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“…The latter three proteins, large T (SVLT), small t and 17kT (Zerrahn et al, 1993) are products of mRNAs generated by alternate splicing from the SVER sequence that we have cloned (retaining the natural pA signals) into the actin cassette. We used SVER rather than SVLT alone by considering that SVLT is essential for cell transformation, while the other antigens stimulate its actions (the spectrum of tumors developing in transgenic mice expressing either SVER or only SVLT could be different; Choi et al, 1988;Ratineau et al, 2000).…”

Section: Application Of the Methodsmentioning

confidence: 99%

‘Designer’ tumors in mice

et al. 2003

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We have developed and tested successfully a general method based on Cre-mediated recombination that can be used for ubiquitous or tissue-specific expression of protein products, including tumor-inducing oncoproteins. Depending on the specificity of a chosen promoter driving cre expression, tumors develop by design in bitransgenic mouse progeny derived by crossing Cre-producing mice with partners carrying a dormant oncogenic transgene (targeted into the 3 0 noncoding region of the cytoplasmic b-actin locus) that becomes functional after excision of a 'floxed' DNA segment. To provide proof-of-principle, we have used as models transgenes encoding the polyomavirus middle T antigen (PVMT) and the T antigens of the SV40 early region (SVER). Cre-dependent activation of widespread SVER expression resulted in hyperplasias or invasive tumors affecting particular visceral smooth muscles, whereas Cre-dependent, mammary gland-specific expression of PVMT-induced adenocarcinomas, according to plan. Unexpectedly, we also encountered spontaneous (Cre-independent) oncogene expression occurring as a rare event, which simulates the initiation of sporadic tumors and leads to PVMT-induced hemangiomas and mammary carcinomas or SVER-induced disseminated sarcomas, thus, revealing particular tissue susceptibilities to the actions of these oncoproteins.

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Independent expression of the transforming amino-terminal domain of SV40 large I antigen from an alternatively spliced third SV40 early mRNA.

Cited by 92 publications

References 55 publications

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

‘Designer’ tumors in mice

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