Professor of Molecular Genetics & Microbiology, Graduate Advisor
Main Office: NMS 2.122
Phone: (512) 471-8415
Alternate Office: NMS 2.262
Phone: (512) 471-5101
The University of Texas at Austin
Department of Molecular Biosciences
2506 Speedway; Stop A5000; NMS 3.316
Austin, TX 78712-1191
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Research Lab Students:
- Ali, Almas - Graduate Student
- Byun, Hyewon - Graduate Student
- Gou, Youngqiang - Graduate Student
- Maitra, Urmila - Graduate Student
- Mann/Simper, Melissa - Graduate Student
- Zhu, Quan - Graduate Student
- Barnett, Anna - Post Doctoral
- Bhadra, Sagar - Post Doctoral
- Byun, Hyewon - Post Doctoral
- Mertz, Jennifer - Post Doctoral
- Mustafa, Farah - Post Doctoral
- Lozano, Mary - Staff
Mouse mammary tumor virus (MMTV) is a retrovirus that induces mammary carcinomas and T-cell lymphomas in mice by insertional mutagenesis. We recently discovered a novel viral protein, Rem, which is involved in the nuclear export and expression of intron-containing viral mRNAs. These results are exciting because MMTV serves as a mouse model for study of another retrovirus, human immunodeficiency virus (HIV), which causes AIDS. Our recent results suggest that Rem has a very unusual trafficking pattern within mammalian cells. Prior to nuclear entry, Rem appears to enter the endoplasmic reticulum (ER), where it is partially glycosylated, and cleaved by signal peptidase. Cleavage appears to yield an HIV Rev-like gene product, SP, as well as a unique product (Rem-CT) of unknown function. Mutations that prevent the correct processing and glycosylation of Rem interfere with SP activity in reporter assays. Rem trafficking through the ER is required for Rem processing and function in the nucleus after signal peptidase cleavage and retrotranslocation of the N-terminal SP out of the ER. Retrotranslocation is associated with endoplasmic reticulum-associated degradation (ERAD). ERAD is a poorly understood cellular process that is responsible for disposal of misfolded proteins. Numerous human diseases, including cancer and neurogeneration, show defects in ERAD. Recent exciting data indicate that the Rem C-terminus has a separate funciton in intrinsic immunity. Finally, we are in the process of developing vectors for gene therapy of breast cancer. Our studies have allowed the extensive mapping of the MMTV genome, which has been evolutionarily selected for optimal expression in the mammary gland. Elimination of viral genes, introduction of reporter genes, and manipulation of tissue-specific promoter elements should enable us to develop and test new vectors for safety and efficacy in mice. Our goal is to provide more specific and less toxic treatments for human breast cancer.
MMTV life cycle - Mouse mammary tumor virus (MMTV) is a retrovirus that has a single-stranded RNA genome. Replication of the viral RNA by virally encoded reverse transcriptase gives a double-stranded DNA copy or provirus with long terminal repeats (LTRs). Integration of the provirus near cellular proto-oncogenes leads to changes in cellular gene expression and either mammary tumors or T-cell lymphomas.
Large MMTV Life Cycle Image
Confocal images of MMTV Rem and cleavage mutants - MMTV Rem has a unique signal peptide that is cleaved by signal peptidase in the ER and then retrotranslocated to the cytoplasm. The cleaved signal peptide is imported into the nucleus, where is it is primarily to the nucleolus. Rem mutants that cannot be cleaved by signal peptidase fail to localize to nucleoli and lack function.
Unique trafficking of the MMTV Rem protein - The MMTV Rem protein has a novel cellular trafficking scheme. After synthesis on membrane-bound polysomes, Rem is processed by signal peptidase into a long signal peptide (SP) and a unique C-terminus (Rem-CT) of unknown function. The SP is retrotranslocated to the cytosol and escapes ER-associated degradation by the proteasome. SP then traffics to the nucleus, where it binds viral RNA to allow increased nuclear export and protein expression.
|2013||Myers L, Joedicke JJ, Carmody AB, Messer RJ, Kassiotis G, Dudley JP, Dittmer U, Hasenkrug KJ, IL-2-independent and TNF-α-dependent expansion of Vβ5+ natural regulatory T cells during retrovirus infection., J. Immunol. 190:5485-5495 view.|
|2012||Byun H, Halani N, Gou Y, Nash AK, Lozano MM, Dudley JP, Requirements for mouse mammary tumor virus Rem signal peptide processing and function, J. Virol. 86:214-225 view.|
|2011||Punkosdy, G. A., M. Blain, M. M. Lozano, J. P. Dudley, R. Ahmed, and E. M. Shevach, Foxp3+ regulatory T cells expand in response to endogenous retroviral superantigens during chronic viral infection, Proc. Natl. Acad. Sci. USA 108:3677-3682 view.|
|2010||Kozak, C., J. A. Mertz, S. Bhadra, M. Palmarini, and J. P. Dudley, Endogenous retroviruses and cancer, In J. P. Dudley (ed.) Retroviruses and Insights into Cancer, Springer, in press.|
|2010||Byun, H., N. Halani, J. A. Mertz, A. F. Ali, M. M. Lozano, and J. P. Dudley, Retroviral Rem protein requires processing by signal peptidase and retrotranslocation for nuclear function, Proc. Natl. Acad. Sci. USA 107:12287-12292 view.|
|2009||Mertz, J. A., A. Chadee, H. Byun, R. Russell, and J. P. Dudley, Mapping of the functional boundaries and secondary structure of the mouse mammary tumor virus Rem-responsive element, J. Biol. Chem. 284:25642-25652 view.|
|2009||Mertz, J. A., M. M. Lozano, and J. P. Dudley. , Rev and Rex proteins of human complex retroviruses function with the MMTV Rem-responsive element, Retrovirology 6:10 view.|
|2006||Bhadra, S., M. M. Lozano, S. M. Payne, and J. P. Dudley., Endogenous MMTV proviruses induce susceptibility to both viral and bacterial pathogens., PLoS Pathogens 2:e128 view.|
|2006||Maitra, U., J. Seo, M. M. Lozano, and J. P. Dudley, Differentiation-induced cleavage of Cutl1/CDP generates a novel dominant-negative isoform that regulates mammary gene expression, Mol. Cell. Biol. 26:7466-7478 view.|
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