ALY Is a Common Coactivator of RUNX1 and c-Myb on the Type B Leukemogenic VirusEnhancer

Mertz, Jennifer A.; Kobayashi, Ryûji; Dudley, Jaquelin P.

doi:10.1128/jvi.02253-06

Cited by 12 publications

(7 citation statements)

References 57 publications

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“…In fact, ALY was originally proposed to play an essential role in the activation of the T-cell receptor ␣ (TCR␣) gene enhancer by interacting with AML-1 and LEF-1 transcription factors (28). Subsequent work also demonstrated that ALY can associate with RUNX1 (AML-1) and c-Myb to trigger the activation of TBLV enhancer (35). Our results further consolidate the role of ALY as key transcriptional modulator.…”

Section: Modulation Of E2f2-dependent Transcriptionalsupporting

confidence: 55%

The Nuclear Protein ALY Binds to and Modulates the Activity of Transcription Factor E2F2

Osinalde

Olea

Mitxelena

et al. 2013

Molecular & Cellular Proteomics

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E2F transcription factors control the expression of genes involved in a variety of essential cellular processes and consequently their activity needs to be tightly regulated. Protein-protein interactions are thought to be key modulators of E2F activity. To gain insight into the mechanisms that regulate the activity of E2F2, we searched for novel proteins that associate with this transcription factor. We show that the nuclear protein ALY (THO complex 4), originally described as a transcriptional co-activator, associates with DNA-bound E2F2 and represses its transcriptional activity. The capacity of ALY to modulate gene expression was analyzed with expression microarrays by characterizing the transcriptome of E2F2 expressing HEK293T cells in which ALY was either overexpressed or silenced. We show that ALY influences the expression of more than 400 genes, including 98 genes bearing consensus E2F motifs. Thus, ALY emerges as a novel E2F2-interacting protein and a relevant modulator of E2F-responsive gene expression. Molecular & Cellular

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Section: Modulation Of E2f2-dependent Transcriptionalsupporting

confidence: 55%

The Nuclear Protein ALY Binds to and Modulates the Activity of Transcription Factor E2F2

Osinalde

Olea

Mitxelena

et al. 2013

Molecular & Cellular Proteomics

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“…TBLV encodes a truncated, non-functional sag gene and lacks transmission to the mammary gland. Infection with TBLV, which has a T-cell-tropic LTR enhancer, induces lymphomas, rather than breast cancer, by insertional mutagenesis (41–43). The infectious TBLV molecular clone (TBLV-WT) differs from MMTV-WT only within the U3 region and does not require sag for replication in vivo (41).…”

Section: Resultsmentioning

confidence: 99%

A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

Singh

Byun

Ali

et al. 2019

mBio

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Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes. IMPORTANCE Complex retroviruses, such as human-pathogenic immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

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“…Despite this link between mRNA export function and proliferation, other activities of ALY could contribute to tumorogenesis. Thus, ALY has also been proposed as a transcriptional coactivator important for c-myc expression in virally induced leukemias and lymphomas [ 26 ], and the yeast homolog Yra1 has been shown to be required for S phase entry [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers

et al. 2011

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BackgroundOne key step in gene expression is the biogenesis of mRNA ribonucleoparticle complexes (mRNPs). Formation of the mRNP requires the participation of a number of conserved factors such as the THO complex. THO interacts physically and functionally with the Sub2/UAP56 RNA-dependent ATPase, and the Yra1/REF1/ALY RNA-binding protein linking transcription, mRNA export and genome integrity. Given the link between genome instability and cancer, we have performed a comparative analysis of the expression patterns of THOC1, a THO complex subunit, and ALY in tumor samples.MethodsThe mRNA levels were measured by quantitative real-time PCR and hybridization of a tumor tissue cDNA array; and the protein levels and distribution by immunostaining of a custom tissue array containing a set of paraffin-embedded samples of different tumor and normal tissues followed by statistical analysis.ResultsWe show that the expression of two mRNP factors, THOC1 and ALY are altered in several tumor tissues. THOC1 mRNA and protein levels are up-regulated in ovarian and lung tumors and down-regulated in those of testis and skin, whereas ALY is altered in a wide variety of tumors. In contrast to THOC1, ALY protein is highly detected in normal proliferative cells, but poorly in high-grade cancers.ConclusionsThese results suggest a differential connection between tumorogenesis and the expression levels of human THO and ALY. This study opens the possibility of defining mRNP biogenesis factors as putative players in cell proliferation that could contribute to tumor development.

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ALY Is a Common Coactivator of RUNX1 and c-Myb on the Type B Leukemogenic VirusEnhancer

Cited by 12 publications

References 57 publications

The Nuclear Protein ALY Binds to and Modulates the Activity of Transcription Factor E2F2

The Nuclear Protein ALY Binds to and Modulates the Activity of Transcription Factor E2F2

A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers

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