Deletions in one domain of the Friend virus-encoded membrane glycoprotein overcome host range restrictions for erythroleukemia

Hoatlin, Maureen E.; Ferro, Frank; Geib, R; Fox, Mary T.; Kozak, Susan L.; Kabat, David

doi:10.1128/jvi.69.2.856-863.1995

Cited by 15 publications

(5 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The human EpoR binds to but is not activated by gp55‐P (Zon et al ., 1992; Hoatlin et al ., 1995). Overall, the human and murine EpoRs are 82% identical in sequence (Jones et al ., 1990) and differ in only three of the 21 amino acids in the membrane‐spanning segment.…”

Section: Resultsmentioning

confidence: 99%

“…The human EpoR is not activated by gp55‐P (Showers et al ., 1993; Hoatlin et al ., 1995); the murine and human EpoRs differ only in three positions in the transmembrane domain and are 82% identical overall (Jones et al ., 1990). Strikingly, mutation of Leu238 to Ser in the transmembrane domain rendered the human EpoR sensitive to activation by gp55‐P.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain

Constantinescu¹

1999

The EMBO Journal

View full text Add to dashboard Cite

The spleen focus forming virus (SFFV) gp55-P envelope glycoprotein specifically binds to and activates murine erythropoietin receptors (EpoRs) coexpressed in the same cell, triggering proliferation of erythroid progenitors and inducing erythroleukemia. Here we demonstrate specific interactions between the single transmembrane domains of the two proteins that are essential for receptor activation. The human EpoR is not activated by gp55-P but by mutation of a single amino acid, L238, in its transmembrane sequence to its murine counterpart serine, resulting in its ability to be activated. The converse mutation in the murine EpoR (S238L) abolishes activation by gp55-P. Computational searches of interactions between the membrane-spanning segments of murine EpoR and gp55-P provide a possible explanation: the face of the EpoR transmembrane domain containing S238 is predicted to interact specifically with gp55-P but not gp55-A, a variant which is much less effective in activating the murine EpoR. Mutational studies on gp55-P M390, which is predicted to interact with S238, provide additional support for this model. Mutation of M390 to isoleucine, the corresponding residue in gp55-A, abolishes activation, but the gp55-P M390L mutation is fully functional. gp55-P is thought to activate signaling by the EpoR by inducing receptor oligomerization through interactions involving specific transmembrane residues.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain

Constantinescu¹

1999

The EMBO Journal

View full text Add to dashboard Cite

show abstract

“…The population of factor-independent BER cells derived (14) in addition to novel components. The results suggest that the early-passaged 1218 virus that was used to infect the BER cells contained at least three different viruses that were able to activate EpoR.…”

Section: Resultsmentioning

confidence: 99%

“…Viruses and cells. EpoR-encoding virions were used to infect the interleukin-3 (IL-3)-dependent hematopoietic cell line BaF3 (29) to produce the BER cells used in this study as previously described (14). BaF3 cells were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum and 5 ϫ 10 Ϫ5 M ␤-mercaptoethanol with 10% WEHI-3 conditioned medium as a source of IL-3.…”

Section: Methodsmentioning

confidence: 99%

An Array of Novel Murine Spleen Focus-Forming Viruses That Activate the Erythropoietin Receptor

Gómez-Lucı́a¹,

Zhi

Nabavi³

et al. 1998

J Virol

View full text Add to dashboard Cite

The Friend spleen focus-forming virus (SFFV) env gene encodes a 409-amino-acid glycoprotein with an apparentM r of 55,000 (gp55) that binds to erythropoietin receptors (EpoR) to stimulate erythroblastosis. We reported previously the in vivo selection during serial passages in mice of several evolutionary intermediates that culminated in the formation of a novel SFFV (M. E. Hoatlin, E. Gomez-Lucia, F. Lilly, J. H. Beckstead, and D. Kabat, J. Virol. 72:3602–3609, 1998). A mouse injected with a retroviral vector in the presence of a nonpathogenic helper virus developed long-latency erythroblastosis, and subsequent viral passages resulted in more pathogenic isolates. The viruses taken from these mice converted an erythropoietin-dependent cell line (BaF3/EpoR) into factor-independent derivatives. Western blot analysis of cell extracts with an antiserum that broadly reacts with murine retroviral envelope glycoproteins suggested that the spleen from the initial mouse with mild erythoblastosis contained an array of viral components that were capable of activating EpoR. DNA sequence analysis of the viral genomes cloned from different factor-independent cell clones revealedenv genes with open reading frames encoding 644, 449, and 187 amino acids. All three env genes contained 3′ regions identical to that of SFFV, including a 6-bp duplication and a single-base insertion that have been shown previously to be critical for pathogenesis. However, the three env gene sequences did not contain any polytropic sequences and were divergent in their 5′ regions, suggesting that they had originated by recombination and partial deletions of endogenously inherited MuLV envsequences. These results suggest that the requirements for EpoR activation by SFFV-related viruses are dependent on sequences at the 3′ end of the env gene and not on the polytropic regions or on the 585-base deletions that are common among the classical strains of SFFV. Moreover, sequence analysis of the different recombinants and deletion mutants revealed that short direct and indirect repeat sequences frequently flanked the deletions that had occurred, suggesting a reverse transcriptase template jumping mechanism for this rapid retroviral diversification.

show abstract

“…Retroviral packaging cell lines -2 (34) and PA12 (37) were used to produce helper-free virions encoding EpoR and gp55 by ping-pong amplification after transfection with retroviral vectors pSFF-EpoRPA11 and pL26K, respectively, as previously described (6,29). The EpoR-encoding virions were used to infect the interleukin-3 (IL-3)-dependent hematopoietic cell line BaF3 (35) to produce the BaF3/EpoR cells (BER) used in this study as previously described (22). The pL26K retroviral vector encoding gp55 of wild-type SFFV (Lilly-Steeves polycythemic strain) has been described elsewhere (31).…”

Section: Methodsmentioning

confidence: 99%

Origin and Rapid Evolution of a Novel Murine Erythroleukemia Virus of the Spleen Focus-Forming Virus Family

Hoatlin¹,

Gómez-Lucı́a²,

Lilly

et al. 1998

J Virol

View full text Add to dashboard Cite

The Friend spleen focus-forming virus (SFFV) env gene encodes a glycoprotein with apparent M r of 55,000 that binds to erythropoietin receptors (EpoR) to stimulate erythroblastosis. A retroviral vector that does not encode any Env glycoprotein was packaged into retroviral particles and was coinjected into mice in the presence of a nonpathogenic helper virus. Although most mice remained healthy, one mouse developed splenomegaly and polycythemia at 67 days; the virus from this mouse reproducibly caused the same symptoms in secondary recipients by 2 to 3 weeks postinfection. This disease, which was characterized by extramedullary erythropoietin-independent erythropoiesis in the spleens and livers, was also reproduced in long-term bone marrow cultures. Viruses from the diseased primary mouse and from secondary recipients converted an erythropoietin-dependent cell line (BaF3/EpoR) into factor-independent derivatives but had no effect on the interleukin-3-dependent parental BaF3 cells. Most of these factor-independent cell clones contained a major Env-related glycoprotein with an M r of 60,000. During further in vivo passaging, a virus that encodes anM r-55,000 glycoprotein became predominant. Sequence analysis indicated that the ultimate virus is a new SFFV that encodes a glycoprotein of 410 amino acids with the hallmark features of classical gp55s. Our results suggest that SFFV-related viruses can form in mice by recombination of retroviruses with genomic and helper virus sequences and that these novel viruses then evolve to become increasingly pathogenic.

show abstract

Deletions in one domain of the Friend virus-encoded membrane glycoprotein overcome host range restrictions for erythroleukemia

Cited by 15 publications

References 68 publications

Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain

Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain

An Array of Novel Murine Spleen Focus-Forming Viruses That Activate the Erythropoietin Receptor

Origin and Rapid Evolution of a Novel Murine Erythroleukemia Virus of the Spleen Focus-Forming Virus Family

Contact Info

Product

Resources

About