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Functional analysis of the mutated Epstein-Barr virus oncoprotein LMP1(69del): implications for a new role of naturally occurring LMP1 variants.
Haematologica. 2003 Dec; 88(12):1324-35.H

Abstract

BACKGROUND AND OBJECTIVES

The role of carboxyterminal deletions of the latent membrane protein-1 (LMP1) in Epstein-Barr virus (EBV) infection and oncogenesis is unclear. Here we describe functional properties of a rare 69-bp LMP1 deletion mutant (LMP1(69del)) isolated from a patient with polyclonal B-cell lymphocytosis.

DESIGN AND METHODS

Colony focus assay was used to evaluate the transforming capacity of LMP1(69del) in comparison to that of wild-type LMP1 from EBV strain B95/8. Transient transfectants of B-, T-, epithelial and 3T3 cells, and stable transfectants with ecdysone-inducible LMP1 expression were produced. The signaling capacity of both LMP1s on nuclear transcription factors NFkappaB and AP-1 were studied. Secretion of matrix metalloproteinase MMP-9, apoptosis, and EBV lytic and latent gene expression were also investigated.

RESULTS

LMP(69del) showed transforming properties comparable to those of the wild-type oncoprotein. Induction of NFkappaB but a markedly reduced influence on AP-1 were observed. Both oncoproteins induced secretion of MMP-9, and enhanced pre-apoptotic effects in Jurkat-T cells leading to increased Fas/Apo-1 and doxorubicin-mediated apoptosis. Furthermore, LMP1(69del) showed a more effective down-regulation of the EBV lytic cycle master gene BZLF1(Zebra) than did wild-type LMP1.

INTERPRETATION AND CONCLUSIONS

(i) LMP1(69del) possesses oncogenic properties, (ii) the observed impaired activity on AP-1 does not interfere with MMP-9 induction, (iii) the enhanced inhibition of BZLF1 could compensate for previously described mutations of our isolate leading to a more lytic phenotype and may be responsible for counteracting permanent virus replication in the chronic active EBV syndrome observed in this patient.

Authors+Show Affiliations

Institute of Hygiene and Social Medicine, University of Innsbruck, Austria. clara.larcher@uibk.ac.atNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14687985

Citation

Larcher, Clara, et al. "Functional Analysis of the Mutated Epstein-Barr Virus Oncoprotein LMP1(69del): Implications for a New Role of Naturally Occurring LMP1 Variants." Haematologica, vol. 88, no. 12, 2003, pp. 1324-35.
Larcher C, Bernhard D, Schaadt E, et al. Functional analysis of the mutated Epstein-Barr virus oncoprotein LMP1(69del): implications for a new role of naturally occurring LMP1 variants. Haematologica. 2003;88(12):1324-35.
Larcher, C., Bernhard, D., Schaadt, E., Adler, B., Ausserlechner, M. J., Mitterer, M., & Huemer, H. P. (2003). Functional analysis of the mutated Epstein-Barr virus oncoprotein LMP1(69del): implications for a new role of naturally occurring LMP1 variants. Haematologica, 88(12), 1324-35.
Larcher C, et al. Functional Analysis of the Mutated Epstein-Barr Virus Oncoprotein LMP1(69del): Implications for a New Role of Naturally Occurring LMP1 Variants. Haematologica. 2003;88(12):1324-35. PubMed PMID: 14687985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional analysis of the mutated Epstein-Barr virus oncoprotein LMP1(69del): implications for a new role of naturally occurring LMP1 variants. AU - Larcher,Clara, AU - Bernhard,David, AU - Schaadt,Eveline, AU - Adler,Barbara, AU - Ausserlechner,Michael J, AU - Mitterer,Manfred, AU - Huemer,Hartwig P, PY - 2003/12/23/pubmed PY - 2006/4/7/medline PY - 2003/12/23/entrez SP - 1324 EP - 35 JF - Haematologica JO - Haematologica VL - 88 IS - 12 N2 - BACKGROUND AND OBJECTIVES: The role of carboxyterminal deletions of the latent membrane protein-1 (LMP1) in Epstein-Barr virus (EBV) infection and oncogenesis is unclear. Here we describe functional properties of a rare 69-bp LMP1 deletion mutant (LMP1(69del)) isolated from a patient with polyclonal B-cell lymphocytosis. DESIGN AND METHODS: Colony focus assay was used to evaluate the transforming capacity of LMP1(69del) in comparison to that of wild-type LMP1 from EBV strain B95/8. Transient transfectants of B-, T-, epithelial and 3T3 cells, and stable transfectants with ecdysone-inducible LMP1 expression were produced. The signaling capacity of both LMP1s on nuclear transcription factors NFkappaB and AP-1 were studied. Secretion of matrix metalloproteinase MMP-9, apoptosis, and EBV lytic and latent gene expression were also investigated. RESULTS: LMP(69del) showed transforming properties comparable to those of the wild-type oncoprotein. Induction of NFkappaB but a markedly reduced influence on AP-1 were observed. Both oncoproteins induced secretion of MMP-9, and enhanced pre-apoptotic effects in Jurkat-T cells leading to increased Fas/Apo-1 and doxorubicin-mediated apoptosis. Furthermore, LMP1(69del) showed a more effective down-regulation of the EBV lytic cycle master gene BZLF1(Zebra) than did wild-type LMP1. INTERPRETATION AND CONCLUSIONS: (i) LMP1(69del) possesses oncogenic properties, (ii) the observed impaired activity on AP-1 does not interfere with MMP-9 induction, (iii) the enhanced inhibition of BZLF1 could compensate for previously described mutations of our isolate leading to a more lytic phenotype and may be responsible for counteracting permanent virus replication in the chronic active EBV syndrome observed in this patient. SN - 1592-8721 UR - https://www.unboundmedicine.com/medline/citation/14687985/Functional_analysis_of_the_mutated_Epstein_Barr_virus_oncoprotein_LMP1_69del_:_implications_for_a_new_role_of_naturally_occurring_LMP1_variants_ L2 - https://antibodies.cancer.gov/detail/CPTC-FOS-4 DB - PRIME DP - Unbound Medicine ER -