Squamous epithelial proliferation induced by walleye dermal sarcoma retrovirus cyclin in transgenic mice

Lairmore, Michael Dale; Stanley, James; Weber, Stacy A.; Holzschu, Donald L.

doi:10.1073/pnas.110024497

Cited by 28 publications

(36 citation statements)

References 37 publications

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“…Analogous to cyclin D3, the WDSV cyclin transgenic mice did not develop thymic hyperplasias. Presumably, the broad phenotype in these transgenic mice, including the severe disruption of normal skin proliferation, is due to biochemical properties of the WDSV cyclin (40). The WEHV rv-cyclins have not been tested for their ability to induce abnormal skin proliferation in transgenic mice.…”

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

“…The distinct phenotypes of transgenic mice suggest that the three mammalian D-type cyclins are not fully redundant and that this system may be particularly suitable for analysis of novel cyclins that induce skin cell proliferation. Transgenic mice expressing the WDSV cyclin from the ker-5 p were recently analyzed (40). In contrast to the mild skin hyperplasia induced by human cyclin D1, D2, or D3 expressed from the same promoter, mice transgenic for the WDSV cyclin had a severe skin hyperplasia, hair loss, and morphological runting.…”

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

“…The important result was that the WDSV cyclin did support growth, suggesting that the rv-cyclins are capable of affecting cell cycle progression and tumor development and growth. Additionally, the WDSV cyclin has been shown to induce cell proliferation in transgenic mice (40). Numerous transgenic mouse models have been used to analyze the oncogenic properties of cellular cyclins (A, D1, D2, D3, and E) and viral cyclins (gammaherpesviruses and WDSV) (5,6,18,33,39,40,44,54,63,64,71,74).…”

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

“…Additionally, the WDSV cyclin has been shown to induce cell proliferation in transgenic mice (40). Numerous transgenic mouse models have been used to analyze the oncogenic properties of cellular cyclins (A, D1, D2, D3, and E) and viral cyclins (gammaherpesviruses and WDSV) (5,6,18,33,39,40,44,54,63,64,71,74). Germane to this review, the expression of cyclins D1, D2, and D3 from the bovine keratin-5 promoter (ker-5 p) induced a common mild skin hyperplasia but a variable cyclin-specific thymic hyperplasia in transgenic mice (63,64).…”

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

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Comparative Pathogenesis of Epsilonretroviruses

Holzschu

LaPierre

Lairmore

2003

J Virol

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Experimental models using mammalian and avian oncogenic retroviruses have led to key advances in the understanding of cell proliferation and oncogenesis and basic principles in cell biology. Since the discovery in 1911 of Rous sarcoma virus (65,66), more than 30 oncogenes have been identified in acutely transforming simple retroviruses (reviewed in references 17 and 62). Retrovirally transduced oncogenes include transcription factors, growth-stimulating factors, receptor molecules, protein tyrosine kinases, protein serine/threonine kinases, and membrane-associated G proteins (62). Each of these retrovirus-encoded oncogenes has a highly conserved cellular counterpart, and many of their human homologs have been implicated in cancers. In contrast to the simple retroviruses, oncogenic complex retroviruses, e.g., human T-cell lymphotropic virus type 1, do not contain typical oncogenes but contain unique regulatory and accessory genes that are believed to promote cancer through their ability to alter cellular gene regulation (1). These studies have contributed greatly to our understanding of eucaryotic cell cycle regulation and cell proliferation, but these processes are still far from understood. Therefore, it is important to continue to develop new research venues for the study of cell proliferation, including new systems to study retrovirus-induced oncogenesis. Piscine and other retroviruses of lower vertebrates represent an untapped resource of model systems to investigate mechanisms of oncogenesis. At least 13 proliferative lesions of fish are tentatively attributed to retroviruses based on the observation of retrovirus-like particles and, in some cases, reverse transcriptase activity in lesions. Interestingly, seven of these lesions are seasonal; i.e., they develop and regress annually, thereby providing unique experimental models for tumor development and naturally occurring tumor death (Table 1) (25). This review focuses on the skin lesions of walleyes (Stizostedion vitreum), i.e., walleye dermal sarcoma (WDS) and walleye epidermal hyperplasia (WEH) and on their associated epsilonretroviruses, WDS virus (WDSV) and WEH viruses 1 and 2 (WEHV1 and WEHV2). WDS AND EPIDERMAL HYPERPLASIAWDS and WEH were first reported on fish from Oneida Lake in New York by Walker (76), who later observed type C retrovirus-like particles in lesions (75, 76). Subsequently, WDS and WEH have been reported on walleyes throughout North America (9, 79). Both WDS and WEH are common in areas of endemicity; nearly 30% of the adult walleyes collected during the spring spawning run from Oneida Lake present WDS in some years, while approximately 10% present WEH. Lesions are present in late fall through early spring, when they regress ( Fig. 1) (2,11,25,60). WDS of feral walleyes is a multifocal, benign skin lesion that can first be seen in the fall as firm, vascularized tumors (Fig. 1). In contrast, WEH is a multifocal hyperproliferative skin disease that can first be seen in the fall as sharply delimited plaques of thickened epidermis (Fig. 1)...

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Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

Section: Wdsv Cyclin Promotes Cell Proliferationmentioning

confidence: 99%

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Comparative Pathogenesis of Epsilonretroviruses

Holzschu

LaPierre

Lairmore

2003

J Virol

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“…Strong evidence supports a role for viral cyclins in the oncogenic processes elicited by these viruses. Viral cyclins drive cellular proliferation (27)(28)(29) and viral replication (30,31). Expression of the KSHV cyclin leads to genomic instability (32), and tumor formation is seen in transgenic mice expressing KSHV cyclin or a distantly related viral cyclin (29,33,34).…”

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confidence: 99%

Cyclin-Cyclin-dependent Kinase Regulatory Response Is Linked to Substrate Recognition

Cuomo

Platt

Pearl

et al. 2011

Journal of Biological Chemistry

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Cyclin/cyclin-dependent kinase (CDK) complexes are critical regulators of cellular proliferation.A complex network of regulatory mechanisms has evolved to control their activity, including activating and inactivating phosphorylation of the catalytic CDK subunit and inhibition through specific regulatory proteins. Primate herpesviruses, including the oncogenic Kaposi sarcoma herpesvirus, encode cyclin D homologues. Viral cyclins have diverged from their cellular progenitor in that they elicit holoenzyme activity independent of activating phosphorylation by the CDK-activating kinase and resistant to inhibition by CDK inhibitors. Using sequence comparison and site-directed mutagenesis, we performed molecular analysis of the cellular cyclin D and the Kaposi sarcoma herpesvirus-cyclin to delineate the molecular mechanisms behind their different behavior. This provides evidence that a surface recognized for its involvement in the docking of CIP/KIP inhibitors is required and sufficient to modulate cyclin-CDK response to a range of regulatory cues, including INK4 sensitivity and CDK-activating kinase dependence. Importantly, amino acids in this region are critically linked to substrate selection, suggesting that a mutational drift in this surface simultaneously affects function and regulation. Together our work provides novel insight into the molecular mechanisms governing cyclin-CDK function and regulation and defines the biological forces that may have driven evolution of viral cyclins.Cyclins are regulatory subunits of the cyclin-dependent family of heterodimeric serine/threonine kinases (CDKs) 2 (1). Specific cyclin-CDK complexes drive progression through the cell division cycle, and their controlled activation is key for appropriate and ordered cell cycle transit (2). Deregulation of cyclin-CDKs is a recognized and probably causative event in cancer development and may be linked to uncontrolled and inappropriate engagement in cell cycle activities (3-5). In normal cells, a dense network of regulatory mechanisms controls duration and timing of these kinases (6, 7). Biochemical studies combined with exemplary crystal structures have provided insights into the mechanisms of cyclin-CDK regulation (8 -10).Cyclins selectively associate with specific CDKs. This association induces extensive conformational changes in the CDK subunit, leading to alignment of residues in the active site as well as rearrangement of the flexible T loop that blocks the entrance to the catalytic cleft in the monomeric CDKs. Phosphorylation of a residue within the T loop by the CDK-activating kinases (CAK) is then required to fully activate the kinase complex (11).A further level of regulation is provided by two classes of inhibitory proteins (CDKIs) (12). The INK4 family, exemplified by p16INK4a (CDKN2A), p15INK4b (CDKN2B), p18INK4c (CDKN2C), and p19INK4d (CDKN2D), selectively binds and affects the activity of CDK4 and CDK6. Cyclin D-CDK4 and cyclin D-CDK6 complexes initiate phosphorylation and inactivation of the retinoblastoma tumor suppresso...

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Intracellular Targeting of Walleye Dermal Sarcoma Virus Orf A (rv-Cyclin)

2001

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Walleye dermal sarcoma virus (WDSV) induces tumors and allows or possibly directs tumor regression. WDSV encodes a putative cyclin homologue, Orf A, and six variant Orf A transcripts have been identified. Northern analysis indicated that a 3.3-kb transcript, encoding full-length Orf A, is the predominant transcript in developing, but not regressing, tumors. Three Orf A proteins, one full-length and two amino-truncated forms, were expressed in mammalian and piscine cells, and their intracellular locations were determined. The full-length form was nuclear and concentrated in interchromatin granule clusters, defined by colocalization with SC-35. The amino-truncated forms were cytoplasmic. Fusion of amino-terminal portions of Orf A to a heterologous protein demonstrated that residues 1-112 were necessary for nuclear localization. Mutation of aa K80 and/or E110 disrupted nuclear localization, suggesting a mechanism similar to that of cellular A- and D-type cyclins for its nuclear import.

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Squamous epithelial proliferation induced by walleye dermal sarcoma retrovirus cyclin in transgenic mice

Cited by 28 publications

References 37 publications

Comparative Pathogenesis of Epsilonretroviruses

Comparative Pathogenesis of Epsilonretroviruses

Cyclin-Cyclin-dependent Kinase Regulatory Response Is Linked to Substrate Recognition

Intracellular Targeting of Walleye Dermal Sarcoma Virus Orf A (rv-Cyclin)

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