A Novel Transgenic Mouse Model of the Human Multiple Myeloma Chromosomal Translocation t(14;16)(q32;q23)

Morito, Naoki; Yoh, Keigyou; Maeda, Atsuko; Nakano, Takako; Fujita, Akiko; Kusakabe, Manabu; Hamada, Michito; Kudo, Takashi; Yamagata, Kunihiro; Takahashi, Satoru

doi:10.1158/0008-5472.can-10-1057

Cited by 44 publications

(42 citation statements)

References 48 publications

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“…Multiple myeloma (MM) is an incurable hematological malignancy derived from plasma cells, and it is the second highest blood cancer and accounts for 2% overall cancer cases. MM is featured with chromosomal translocations which lead to overexpression of several key genes, including the transcription factor c-Maf (13,14) which promotes MM cell by guest on May 12, 2018 http://www.jbc.org/ Downloaded from 3 proliferation and development (15,16). In the present study, we found that TMEPAI induces the ubiquitination and degradation of c-Maf and induces MM cell apoptosis independent of TGF-β signaling.…”

supporting

confidence: 55%

“…The transcription factor c-Maf is an oncogene in myelomagenesis (15) and an independent factor in the poor prognosis of MM patients. The c-Maf stability was modulated via the ubiquitin-proteasome pathway (17).…”

Section: Discussionmentioning

confidence: 99%

“…c-Maf is a transcription factor that induces myelomagenesis (15) and it could be degraded via both proteasomes and lysosomes (17). Our previous studies have showed that ubiquitin ligase HERC4 and ubiquitin-conjugating enzyme UBE2O lead to c-Maf degradation (13,18).…”

Section: Tmepai Induces C-maf Degradationmentioning

confidence: 99%

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The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Liu

et al. 2018

Journal of Biological Chemistry

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Transmembrane prostate androgen-induced protein (TMEPAI, also called prostate transmembrane protein, androgen induced 1 [PMEPA1]), is a type I transmembrane (TM) protein, but its cellular function is largely unknown. Here, studying factors influencing the stability of c-Maf, a critical transcription factor in multiple myeloma (MM), we found that TMEPAI induced c-Maf degradation. We observed that TMEPAI recruited neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), a WW domain-containing ubiquitin ligase, to c-Maf, leading to its degradation through the proteasomal pathway. Further investigation revealed that TMEPAI interacts with NEDD4 via its conserved PY motifs. Alanine substitution or deletion of these motifs abrogated the TMEPAI complex formation with NEDD4, resulting in failed c-Maf degradation. Functionally, TMEPAI suppressed the transcriptional activity of c-Maf. Of note, increased TMEPAI expression was positively associated with the overall survival of MM patients. Moreover, (1). In addition to androgen, TMEPAI expression is also stimulated by some growth factors such as epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) (2). The expression profiling found that TMEPAI is overexpressed in solid cancers including prostate cancer , lung (3,4), breast (3,5) and ovarian cancers (6), and rental cell carcinoma (7), but it is not detectable in liquid cancers such as leukemia and lymphoma samples (7). The specific expression pattern suggests that TMEPAI might function differently upon specific cancer types. For example, TMEPAI displays as a tumor suppressor in prostate cancer progression because silence of TMEPAI leads to accelerated proliferation of prostate cancer cells (8) while expression of TMEPAI inhibits prostate cancer cell growth (9) and prevents its bone metastasis (10). However, TMEPAI acts as an oncogene and promotes proliferation and survival of lung and breast cancers. TMEPAI mediates the degradation of receptor-activated SMAD and activates non-canonical PI3K/AKT signaling transduction thus promoting TGF-β-dependent cell growth and metastasis of triple negative breast cancer (3). In lung cancer cells, TMEPAI not only increases cancer cell proliferation, migration and invasion (11,12) but also enhances tumorigenicity and the epithelial-mesenchymal transition (EMT) of lung cancer cells (4). These actions were associated with TMEPAI-induced TGF-β degradation in lysosomes and TMEPAI-induced reactive oxygen species and insulin receptor substrate-1 (4). In contrast, knockdown of TMEPAI enhances Smad2 phosphorylation and significantly suppressed lung cancer cell proliferation in the presence of TGF-β. All the above results collectively suggest that TMEPAI can promote or suppress cancer cell proliferation and tumor growth depending on the cancer types but the TGF-β signaling pathway is a key factor.Hematological malignancies are a collection of blood cancers including leukemia, lymphoma and multiple myeloma in which TMEPAI is less expressed (7), but the fun...

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supporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Liu

et al. 2018

Journal of Biological Chemistry

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“…It was shown that Maf proteins can transform primary cells (Nishizawa et al, 2003;Pouponnot et al, 2006). Their oncogenic activity was also demonstrated in multiple myeloma cell lines (Hurt et al, 2004) and in mice (Morito et al, 2006(Morito et al, , 2011.…”

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confidence: 98%

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

Hamze

Bonnavion

et al. 2011

Oncogene

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MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic a-and b-cells. However, the role of MafB in the control of adult islet-cell proliferation remains unknown. Considering its oncogenic potential in several other tissues, we investigated the possible alteration of its expression in adult mouse b-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in B30% of adaptive b-cells both in gestational female mice and in mice fed with a high-fat diet. Importantly, reactivated MafB expression was also observed in the early b-cell lesions and insulinomas that developed in b-cell specific Men1 mutant mice, appearing in >80% of b-cells in hyperplasic or dysplastic islets from the mutant mice >4 months of age. Moreover, MafB expression could be induced by glucose stimulation in INS-1 rat insulinoma cells. The induction was further reinforced following Men1 knockdown by siRNA. Furthermore, MafB overexpression in cultured bTC3 cells enhanced cell foci formation both in culture medium and on soft agar, accompanied with the increased expression of Cyclin B1 and D2. Conversely, MafB downregulation by siRNA transfection reduced BrdU incorporation in INS-1E cells. Taken together, our data reveal that Men1 inactivation leads to MafB reexpression in mouse b-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult b-cell proliferation and Men1-related tumorigenesis.

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“…In addition, they display a more indolent tumor growth, with tumor development that takes up to 18 months, that allows for treatment initiation at a stage more resembling to the clinical situation. Several of such models have been reported, including transgenic Eμ-c-MAF and Eμ-XBP1s mice that overexpress these myeloma-associated genes in an Eμ-dependent B-cell specific manner [149,150]. In addition, Chesi et al generated Vk*MYC transgenic mice in which the activation of MYC is under the control of the Igκ light chain gene regulatory elements, developing tumors that are highly homologous to those observed in human MM [151].…”

Section: Discussionmentioning

confidence: 99%

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Binsfeld

Fostier

Muller

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models.

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A Novel Transgenic Mouse Model of the Human Multiple Myeloma Chromosomal Translocation t(14;16)(q32;q23)

Cited by 44 publications

References 48 publications

The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

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