C3H Mouse Mammary Tumor Virus Superantigen Function Requires a Splice Donor Site in the Envelope Gene

Mustafa, Farah; Lozano, Mary M.; Dudley, Jaquelin P.

doi:10.1128/jvi.74.20.9431-9440.2000

Cited by 20 publications

(30 citation statements)

References 47 publications

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“…The stably transfected cells (XC/HYB-MTV) [30] were injected intraperitoneally into BALB/c and Mtv -null weanlings. Wild-type mice developed mammary tumors with an incidence of 90% and an average latency of 8.9 ± 2.2 mo, whereas Mtv -null mice had a 10% mammary tumor incidence (three of 29 animals inoculated) with an average latency of 12.7 ± 3.2 mo (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

et al. 2006

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Most inbred mice carry germline proviruses of the retrovirus, mouse mammary tumor virus (MMTV) (called Mtvs), which have multiple replication defects. A BALB/c congenic mouse strain lacking all endogenous Mtvs (Mtv-null) was resistant to MMTV oral and intraperitoneal infection and tumorigenesis compared to wild-type BALB/c mice. Infection of Mtv-null mice with an MMTV-related retrovirus, type B leukemogenic virus, also resulted in severely reduced viral loads and failure to induce T-cell lymphomas, indicating that resistance is not dependent on expression of a superantigen (Sag) encoded by exogenous MMTV. Resistance to MMTV in Mtv-null animals was not due to neutralizing antibodies. Further, Mtv-null mice were resistant to rapid mortality induced by intragastric inoculation of the Gram-negative bacterium, Vibrio cholerae, but susceptibility to Salmonella typhimurium was not significantly different from BALB/c mice. Susceptibility to both MMTV and V. cholerae was reconstituted by the presence of any one of three endogenous Mtvs located on different chromosomes and was associated with increased pathogen load. One of these endogenous proviruses is known to encode only Sag. Therefore, Mtv-encoded Sag appears to provide a unique genetic susceptibility to specific viruses and bacteria. Since human endogenous retroviruses also encode Sags, these studies have broad implications for pathogen-induced responses in mice and humans.

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Section: Resultsmentioning

confidence: 99%

Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

et al. 2006

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“…The MMTV superantigen (Sag) is translated from a singly spliced RNA to give expression at the surface of antigen-presenting cells in conjunction with major histocompatibility complex class II protein (39). Sag is required for the amplification of viral expression in B and T cells and transmission of the infection among mammary gland cells (20,21).…”

Section: Discussionmentioning

confidence: 99%

Mouse Mammary Tumor Virus Encodes a Self-Regulatory RNA Export Protein and Is a Complex Retrovirus

Mertz

Simper

Lozano

et al. 2005

J Virol

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112

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Mouse mammary tumor virus (MMTV) has been classified as a simple retrovirus with two accessory genes, dut and sag. Cloned MMTV proviruses carrying a trimethoprim (trim) cassette in the envelope gene were defective for Gag protein production and the nuclear export of unspliced gag-pol RNA. Complementation experiments indicated that a trans-acting product was responsible for the Gag defect of such mutants. Analysis of MMTV-infected cells revealed the presence of a novel, doubly spliced RNA that encodes a putative product of 301 amino acids. Overexpression of cDNA from this RNA increased Gag levels from env mutant proviruses or reporter gene expression from unspliced mRNAs and allowed detection of a 33-kDa protein product, which has been named regulator of export of MMTV mRNA, or Rem. The Rem N terminus has motifs similar to the Rev-like export proteins of complex retroviruses, and mutation of the nuclear localization signal (NLS) abolished RNA export and detection within the nucleus. The Rem C terminus has few identifiable features, but removal of this domain increased Rem-mediated export, suggesting an autoregulatory function. A reporter vector developed from the 3 end of the MMTV provirus was Rem responsive and required both the presence of the MMTV env-U3 junction and a functional Crm1 pathway. The identification of a third accessory protein from a doubly spliced transcript suggests that MMTV is the first murine complex retrovirus to be documented. Manipulation of the MMTV genome may provide mouse models for human retroviral diseases, such as AIDS.

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“…Lymphocytes were isolated and analyzed as described previously (31). Antibodies used for staining were obtained from Pharmingen.…”

Section: Methodsmentioning

confidence: 99%

The Homeodomain Protein CDP Regulates Mammary-Specific Gene Transcription and Tumorigenesis

Zhu

Maitra

Johnston

et al. 2004

Molecular and Cellular Biology

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The CCAAT-displacement protein (CDP) has been implicated in developmental and cell-type-specific regulation of many cellular and viral genes. We previously have shown that CDP represses mouse mammary tumor virus (MMTV) transcription in tissue culture cells. Since CDP-binding activity for the MMTV long terminal repeat declines during mammary development, we tested whether binding mutations could alter viral expression. Infection of mice with MMTV proviruses containing CDP binding site mutations elevated viral RNA levels in virgin mammary glands and shortened mammary tumor latency. To determine if CDP has direct effects on MMTV transcription rather than viral spread, virgin mammary glands of homozygous CDP-mutant mice lacking one of three Cut repeat DNA-binding domains (⌬CR1) were examined by reverse transcription-PCR. RNA levels of endogenous MMTV as well as ␣-lactalbumin and whey acidic protein (WAP) were elevated. Heterozygous mice with a different CDP mutation that eliminated the entire C terminus and the homeodomain (⌬C mice) showed increased levels of MMTV, ␤-casein, WAP, and ␣-lactalbumin RNA in virgin mammary glands compared to those from wild-type animals. No differences in amounts of WDNM1, -casein, or glyceraldehyde-3-phosphate dehydrogenase RNA were observed between the undifferentiated mammary tissues from wild-type and mutant mice, indicating the specificity of this effect. These data show independent contributions of different CDP domains to negative regulation of differentiation-specific genes in the mammary gland.The CCAAT displacement protein (CDP) family constitutes a highly conserved group of homeoproteins that are involved in cell growth, differentiation, and development. CDP (also known as Cut in Drosophila melanogaster, Clox in dogs, and Cux in mice) is a transcriptional repressor that contains four DNA-binding domains, three Cut repeats (CR1, -2, and -3), and a homeodomain (32). CDP is involved in suppressing transcription from many cellular genes, including c-myc, transforming growth factor ␤ type II receptor, phox, CD8, immunoglobulin heavy chain, and T-cell receptor ␤-chain (3,7,12,19,22,46), as well as viral genes, including those from mouse mammary tumor virus (MMTV) and human papillomaviruses (HPVs) (1, 55). In addition, CDP has been implicated as a tumor suppressor gene in human breast carcinomas and uterine leiomyomas (28,47,53).Many genes regulated by CDP are expressed in highly differentiated cells. CDP DNA-binding activity is downregulated during B-cell and myeloid cell development (22, 46), and CDP expression in the kidney is inversely related to the degree of cellular differentiation (44). We have shown that CDP is a repressor of MMTV long terminal repeat (LTR) reporter gene expression in cultured cell lines and that CDP-binding activity to the LTR declines during mammary gland development (55).These results suggest that CDP functions as a transcriptional repressor that inhibits expression of differentiation-specific genes in several tissues.The retrovirus MMTV is a paradigm fo...

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C3H Mouse Mammary Tumor Virus Superantigen Function Requires a Splice Donor Site in the Envelope Gene

Cited by 20 publications

References 47 publications

Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

Mouse Mammary Tumor Virus Encodes a Self-Regulatory RNA Export Protein and Is a Complex Retrovirus

The Homeodomain Protein CDP Regulates Mammary-Specific Gene Transcription and Tumorigenesis

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