Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

Fluck, Michele M.; Schaffhausen, Brian

doi:10.1128/mmbr.00009-09

Cited by 142 publications

(164 citation statements)

References 349 publications

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“…Probably as a consequence of the PyMT-mediated activation of PI3Ka 29 , we observed that orthotopically transplanted PyMT þ ;Rras2 À / À MECs could form tumours more efficiently than the immortalized breast cancer cells used in prior assays (Fig. 7d,e).…”

Section: R-ras2 Uses Different Downstream Effectors During Metastasismentioning

confidence: 59%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss-and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.

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Section: R-ras2 Uses Different Downstream Effectors During Metastasismentioning

confidence: 59%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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“…However, we hypothesize that ALTO/MT proteins likely perform related functions despite this low sequence and structural conservation, similar to many examples of disordered proteins that can accomplish very similar biological tasks (34). Consistent with this possibility of similar function, the second exons of MT proteins from MPyV and HamsterPyV are less than 20% identical, yet both MTs use short linear sequences, such as phosphatidylinositol-3 kinase motifs, whose location is not conserved between the two proteins but retention of these motifs has been shown to be important for the functions of both proteins (22). We have also identified putative short linear motifs among closely related ALTO proteins of MCPyV-related viruses (SI Appendix, Alignment S2).…”

Section: Subfunctionalizationmentioning

confidence: 78%

“…The main transforming activity of MPyV is encoded by the middle T antigen (MT), which splices the first exon corresponding to ST to the overprinting frame in exon 2. Studies of MT in MPyV have led to discoveries of phosphotyrosine kinases (PTK) and phosphoinositide 3-kinase (PI3K) signaling (9,22). Although ALTO does not appear to be essential for viral genome replication, we find that it is mutated in many cancer tissues and that elucidation of its function may uncover new roles for ALTO in MCPyV manipulation of human cell signaling and perhaps in cancer development.…”

Section: Discussionmentioning

confidence: 91%

“…Initial similarity searches [using tblastn (21)] indicated that ALTO was exclusively present in MCPyV and three other hominoid polyomaviruses (ChimpPyV1, ChimpPyV2, and GorillaPyV1). However, we also noted that, like ALTO, the second exon of MPyV MT is the result of overprinting onto the LT gene (22). We thus considered whether ALTO and the second exon of MT are evolutionarily related, representing a single gene birth.…”

Section: Resultsmentioning

confidence: 99%

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Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes

Carter

Daugherty

Qi³

et al. 2013

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

148

149

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Many viruses use overprinting (alternate reading frame utilization) as a means to increase protein diversity in genomes severely constrained by size. However, the evolutionary steps that facilitate the de novo generation of a novel protein within an ancestral ORF have remained poorly characterized. Here, we describe the identification of an overprinting gene, expressed from an Alternate frame of the Large T Open reading frame (ALTO) in the early region of Merkel cell polyomavirus (MCPyV), the causative agent of most Merkel cell carcinomas. ALTO is expressed during, but not required for, replication of the MCPyV genome. Phylogenetic analysis reveals that ALTO is evolutionarily related to the middle T antigen of murine polyomavirus despite almost no sequence similarity. ALTO/MT arose de novo by overprinting of the second exon of T antigen in the common ancestor of a large clade of mammalian polyomaviruses. Taking advantage of the low evolutionary divergence and diverse sampling of polyomaviruses, we propose evolutionary transitions that likely gave birth to this protein. We suggest that two highly constrained regions of the large T antigen ORF provided a start codon and C-terminal hydrophobic motif necessary for cellular localization of ALTO. These two key features, together with stochastic erasure of intervening stop codons, resulted in a unique protein-coding capacity that has been preserved ever since its birth. Our study not only reveals a previously undefined protein encoded by several polyomaviruses including MCPyV, but also provides insight into de novo protein evolution. gene evolution | synonymous substitution | disordered motifs T he birth of new genes has fascinated biologists for decades. Although the steps required to generate a new gene by gene duplication or gene rearrangement have been characterized, less is known about the birth of new genes de novo. One particularly intriguing mechanism of de novo gene birth is via "overprinting," in which a novel overprinting gene is encoded as an alternate ORF within an ancestral "overprinted" gene (1). Overprinting results in two unrelated functional proteins encoded as overlapping ORFs within the same DNA sequence. However, the origins of such a complex evolutionary solution have remained elusive.Viruses appear to be especially adept at this form of evolutionary innovation. This frequent use of overprinting is likely the result of the severe constraints imposed on viral genome size, making gene innovation more likely to occur as overprinting rather than within a noncoding region (2). Due to the numerous examples of overprinting in single-stranded RNA viruses, a great deal of research has focused in particular on this class of viruses (3-6). However, small DNA viruses, such as adenoviruses, papillomaviruses, and polyomaviruses, have a similar requirement to maximize the coding capacity of their genomes. In this study, we have taken advantage of our identification of an overprinting gene born in the ancestor of a large clade of polyomaviruses to investigate the...

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“…The effects of dietary energy balance alterations, such as CR and diet-induced obesity (DIO), on ERa low luminal breast cancer are poorly characterized, at least in part due to a paucity of relevant animal models of this intrinsic subtype of breast cancer. Comparative oncogenomic studies on human and mouse mammary tumors show that tumors from the polyoma middle-T antigen transgenic mice cluster closely with human luminal B breast tumors and share many of the pathological and molecular hallmarks of human luminal B tumors (Herschkowitz et al 2007, Fluck & Schaffhausen 2009, Zhu et al 2011. Furthermore, the Met1 cell line, derived from a spontaneous tumor from a polyoma middle-T antigen transgenic mouse, progressively loses ER and progesterone receptor positivity with tumor progression, therefore providing a rapid and relevant model for studying ERa low luminal mammary tumor progression when orthotopically transplanted into syngeneic mice (Lin et al 2003, Borowsky et al 2005, Namba et al 2006, Bonuccelli et al 2009.…”

Section: Introductionmentioning

confidence: 99%

IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

Ford¹,

Núñez²,

Holcomb³

et al. 2012

Endocrine-Related Cancer

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Luminal breast tumors with little or no estrogen receptor a expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the IGF1-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal transition (EMT), and chemokine expression. Liver-specific IGF1-deficient (LID) and littermate control (LC) mice were administered control, DIO, or 30% CR diets for 3 months before orthotopic injection of Met1 cells. Tumors grew for 1 month and then were assessed for Akt pathway activation and mRNA expression of chemokine and EMT constituents. LID mice, regardless of diet, displayed reduced Met1 tumor growth and downregulated Akt, EMT, and chemokine pathways. CR, relative to control, reduced serum IGF1 and Met1 tumor growth in LC (but not LID) mice. DIO, relative to control, increased Met1 tumor growth and chemokine expression in LID mice, and had no effect on serum IGF1 or pAkt or cyclin D1 expression in either genotype. Thus, circulating IGF1 (in association with Akt, EMT, and chemokines) regulated Met1 tumor growth. While the anticancer effects of CR were largely IGF1-dependent, the procancer effects of DIO manifested only when circulating IGF1 levels were low. Thus, in a murine model of luminal breast cancer, IGF1 and its downstream signaling pathway, EMT, and chemokines present possible mechanistic regulatory targets. Transplanted MMTV1 Wnt1 mammary tumor growth was also reduced in LID mice, relative to LC mice, suggesting that the IGF1 effects on mammary tumor growth are not limited to Met1 tumors.

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Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

Cited by 142 publications

References 349 publications

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes

IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

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