A novel role of MNT as a negative regulator of REL and the NF-κB pathway.

MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it.

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas.

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified.

Suppression of FGFR3- and MYC-dependent oncogenesis by tubacin: association with HDAC6-dependent and independent activities.

Fibroblast growth factor receptor 3 (FGFR3) is amplified, translocated or mutated in a number of different human cancer types, but most commonly in bladder cancers. We previously found that the accumulation of FGFR3 is dependent on histone deacetylase 6 (HDAC6). Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3.

Mnt modulates Myc-driven lymphomagenesis.

The transcriptional represser Mnt is a functional antagonist of the proto-oncoprotein Myc. Both Mnt and Myc utilise Max as an obligate partner for DNA binding, and Myc/Max and Mnt/Max complexes compete for occupancy at E-box DNA sequences in promoter regions. We have previously shown in transgenic mouse models that the phenotype and kinetics of onset of haemopoietic tumours varies with the level of Myc expression.

MNT and Emerging Concepts of MNT-MYC Antagonism.

MYC family proteins play fundamental roles in stem and progenitor cell homeostasis, morphogenesis and cancer. As expected for proteins that profoundly affect the fate of cells, the activities of MYC are regulated at a multitude of levels. One mechanism with the potential to broadly affect the activities of MYC is transcriptional antagonism by a group of MYC-related transcriptional repressors.

HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia.

Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6.

Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes.

Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation.

The activities of MYC, MNT and the MAX-interactome in lymphocyte proliferation and oncogenesis.

The MYC family of proteins plays essential roles in embryonic development and in oncogenesis. Efforts over the past 30 years to define the transcriptional activities of MYC and how MYC functions to promote proliferation have produced evolving models of MYC function. One picture that has emerged of MYC and its partner protein MAX is of a transcription factor complex with a seemingly unique ability to stimulate the transcription of genes that are epigenetically poised for transcription and to amplify the transcription of actively transcribed genes.

Control of vertebrate development by MYC.

The study of MYC has led to pivotal discoveries in cancer biology, induced pluripotency, and transcriptional regulation. In this review, continuing advances in our understanding of the function of MYC as a transcription factor and how its transcriptional activity controls normal vertebrate development and contributes to developmental disorders is discussed.

A repressor protein, Mnt, is a novel negative regulator of vascular smooth muscle cell hypertrophy by angiotensin II and neointimal hyperplasia by arterial injury.

Objective: The Max-interacting protein Mnt is a transcriptional repressor that can antagonize the transcriptional and proliferation-related activities of Myc. Here, we tested the hypothesis that Mnt is a negative regulator of pathological vascular remodeling.

Methods: Adenovirus encoding Mnt or control GFP was infected to cultured rat vascular smooth muscle cells (VSMC) and carotid arteries after a balloon angioplasty.

A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis.

Mnt (Max's next tango) is a Max-interacting transcriptional repressor that can antagonize both the proproliferative and proapoptotic functions of Myc in vitro. To ascertain the physiologically relevant functions of Mnt and to help define the relationship between Mnt and Myc in vivo, we generated a series of mouse strains in which Mnt was deleted in T cells in the absence of endogenous c-Myc or in the presence of ectopic c-Myc. We found that apoptosis caused by loss of Mnt did not require Myc but that ectopic Myc expression dramatically decreased the survival of both Mnt-deficient T cells in vivo and Mnt-deficient MEFs in vitro.

Disruption of a Sox9-β-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II.

Mutations in fibroblast growth factor (FGF) receptors are responsible for a variety of skeletal birth defects, but the underlying mechanisms responsible remain unclear. Using a mouse model of thanatophoric dysplasia type II in which FGFR3(K650E) expression was directed to the appendicular skeleton, we show that the mutant receptor caused a block in chondrocyte differentiation specifically at the prehypertrophic stage. The differentiation block led to a severe reduction in hypertrophic chondrocytes that normally produce vascular endothelial growth factor, which in turn was associated with poor vascularization of primary ossification centers and disrupted endochondral ossification.

Differential regulation of N-Myc and c-Myc synthesis, degradation, and transcriptional activity by the Ras/mitogen-activated protein kinase pathway.

Myc transcription factors are important regulators of proliferation and can promote oncogenesis when deregulated. Deregulated Myc expression in cancers can result from MYC gene amplification and translocation but also from alterations in mitogenic signaling pathways that affect Myc levels through both transcriptional and post-transcription mechanisms. For example, mutations in Ras family GTPase proteins that cause their constitutive activation can increase cellular levels of c-Myc by interfering with its rapid proteasomal degradation.

Sequential and coordinated actions of c-Myc and N-Myc control appendicular skeletal development.

Background: During limb development, chondrocytes and osteoblasts emerge from condensations of limb bud mesenchyme. These cells then proliferate and differentiate in separate but adjacent compartments and function cooperatively to promote bone growth through the process of endochondral ossification. While many aspects of limb skeletal formation are understood, little is known about the mechanisms that link the development of undifferentiated limb bud mesenchyme with formation of the precartilaginous condensation and subsequent proliferative expansion of chondrocyte and osteoblast lineages.

OX40 engagement stabilizes Mxd4 and Mnt protein levels in antigen-stimulated T cells leading to an increase in cell survival.

OX40 engagement on activated T cells leads to increased proliferation, expansion and survival of Ag-specific T cells. Direct ex vivo examination of Ag-stimulated murine T cells show that the Myc antagonists, Mxd4 and Mnt, are transiently upregulated and translocated to the nucleus following OX40 engagement and may be involved in suppressing cell death. Both Mxd4 and Mnt are upregulated following OX40 stimulation through increased protein stability and we identify a critical phosphorylation site in Mxd4 that controls Mxd4 stability.

The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects.

Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we show that birth defect and cancer-associated FGFR2 mutants promote DNA-damage signaling and p53-dependent senescence in primary mouse and human cells.

Development of human gene reporter cell lines using rAAV mediated homologous recombination.

Understanding mechanisms of gene regulation has broad therapeutic implications for human disease. Here we describe a novel method for generating human cell lines that serve as reporters of transcriptional activity. This method exploits the ability of recombinant adeno-associated virus to mediate the insertion of exogenous DNA sequences into specific genomic loci through homologous recombination.

Activities of N-Myc in the developing limb link control of skeletal size with digit separation.

The developing limb serves as a paradigm for studying pattern formation and morphogenetic cell death. Here, we show that conditional deletion of N-Myc (Mycn) in the developing mouse limb leads to uniformly small skeletal elements and profound soft-tissue syndactyly. The small skeletal elements are associated with decreased proliferation of limb bud mesenchyme and small cartilaginous condensations, and syndactyly is associated with a complete absence of interdigital cell death.

The MAX-interacting transcription factor network.

The small bHLHZip protein MAX functions at the center of a transcription factor network that governs many aspects of cell behavior, including cell proliferation and tumorigenesis. MAX serves as a cofactor for DNA binding by the various members of this network, which include the MYC family of oncoproteins and a group of putative MYC antagonists that include MNT, MXD1-4 (formerly MAD1, MXI1, MAD3 and MAD4) and MGA. The many heterodimerization partners of MAX raises questions concerning the dynamics of MAX interactions and the functional consequences of the switching of Max partners.

Inflammatory disease and lymphomagenesis caused by deletion of the Myc antagonist Mnt in T cells.

Mnt is a Max-interacting protein that can antagonize the activities of Myc oncoproteins in cultured cells. Mnt null mice die soon after birth, but conditional deletion of Mnt in breast epithelium leads to tumor formation. These and related data suggest that Mnt functions as a tumor suppressor.

N-Myc functions in transcription and development.

N-Myc is a member of the Myc family of proteins, which are best known for their potent oncogenic activities and association with a large proportion of human cancers. Intense scrutiny of the oncogenic properties of Myc family proteins over the last several decades has revealed a great deal about their transcriptional and oncogenic activities. Myc proteins have broad effects on transcription and can stimulate a variety of cell behaviors that contribute to the malignant phenotype.

Of Myc and Mnt.

Deregulation of Myc expression is a common feature in cancer and leads to tumor formation in experimental model systems. There are several potential barriers that Myc must overcome in order to promote tumorigenesis, including its propensity to sensitize many cell types to apoptotic cell death. Myc activities appear also to be constrained and fine-tuned by a set of proteins that include the Mxd (formerly named Mad) family and the related protein Mnt.