scholarly journals Akt Regulates Basic Helix-Loop-Helix Transcription Factor-Coactivator Complex Formation and Activity during Neuronal Differentiation

2003 ◽  
Vol 23 (13) ◽  
pp. 4417-4427 ◽  
Author(s):  
Anne B. Vojtek ◽  
Jennifer Taylor ◽  
Stacy L. DeRuiter ◽  
Jenn-Yah Yu ◽  
Claudia Figueroa ◽  
...  
Keyword(s):  
Growth Factors ◽  
Complex Formation ◽  
Neuronal Differentiation ◽  
Protein Function ◽  
Bhlh Protein ◽  
Akt Inhibitor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Peptide Growth Factors ◽  
Bhlh Proteins

ABSTRACT Neural basic helix-loop-helix (bHLH) transcription factors regulate neurogenesis in vertebrates. Signaling by peptide growth factors also plays critical roles in regulating neuronal differentiation and survival. Many peptide growth factors activate phosphatidylinositol 3-kinase (PI3K) and subsequently the Akt kinases, raising the possibility that Akt may impact bHLH protein function during neurogenesis. Here we demonstrate that reducing expression of endogenous Akt1 and Akt2 by RNA interference (RNAi) reduces neuron generation in P19 cells transfected with a neural bHLH expression vector. The reduction in neuron generation from decreased Akt expression is not solely due to decreased cell survival, since addition of the caspase inhibitor z-VAD-FMK rescues cell death associated with loss of Akt function but does not restore neuron formation. This result indicates that Akt1 and Akt2 have additional functions during neuronal differentiation that are separable from neuronal survival. We show that activated Akt1 enhances complex formation between bHLH proteins and the transcriptional coactivator p300. Activated Akt1 also significantly augments the transcriptional activity of the bHLH protein neurogenin 3 in complex with the coactivators p300 or CBP. In addition, inhibition of endogenous Akt activity by the PI3K/Akt inhibitor LY294002 abolishes transcriptional cooperativity between the bHLH proteins and p300. We propose that Akt regulates the assembly and activity of bHLH-coactivator complexes to promote neuronal differentiation.

scholarly journals Modulation of Basic Helix-Loop-Helix Transcription Complex Formation by Id Proteins during Neuronal Differentiation

2001 ◽  
Vol 277 (11) ◽  
pp. 9118-9126 ◽  
Author(s):  
Annika Jögi ◽  
Paula Persson ◽  
Anna Grynfeld ◽  
Sven Påhlman ◽  
Håkan Axelson
Keyword(s):  
Complex Formation ◽  
Neuronal Differentiation ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Id Proteins

scholarly journals Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer.

1994 ◽  
Vol 14 (9) ◽  
pp. 6153-6163 ◽  
Author(s):  
T Genetta ◽  
D Ruezinsky ◽  
T Kadesch
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Zinc Finger Protein ◽  
Immunoglobulin Heavy Chain ◽  
Bhlh Protein ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Box ◽  
Bhlh Proteins

The activity of the immunoglobulin heavy-chain (IgH) enhancer is restricted to B cells, although it binds both B-cell-restricted and ubiquitous transcription factors. Activation of the enhancer in non-B cells upon overexpression of the basic helix-loop-helix (bHLH) protein E2A appears to be mediated not only by the binding of E2A to its cognate E box but also by the resulting displacement of a repressor from that same site. We have identified a "two-handed" zinc finger protein, denoted ZEB, the DNA-binding specificity of which mimics that of the cellular repressor. By employing a derivative E box that binds ZEB but not E2A, we have shown that the repressor is active in B cells and the IgH enhancer is silenced in the absence of binding competition by bHLH proteins. Hence, we propose that a necessary prerequisite of enhancer activity is the B-cell-specific displacement of a ZEB-like repressor by bHLH proteins.

scholarly journals Basic Helix-Loop-Helix Proteins Bind to TrkB and p21Cip1 Promoters Linking Differentiation and Cell Cycle Arrest in Neuroblastoma Cells

2004 ◽  
Vol 24 (7) ◽  
pp. 2662-2672 ◽  
Author(s):  
Yuhui Liu ◽  
Mario Encinas ◽  
Joan X. Comella ◽  
Martí Aldea ◽  
Carme Gallego
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Neuronal Differentiation ◽  
Ectopic Expression ◽  
Neurotrophin Receptor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Cycle Arrest ◽  
E Box ◽  
Bhlh Proteins

ABSTRACT Differentiation of precursor into specialized cells involves an increasing restriction in proliferative capacity, culminating in cell cycle exit. In this report we used a human neuroblastoma cell line to study the molecular mechanisms that coordinate cell cycle arrest and neuronal differentiation. Exposure to retinoic acid (RA), a differentiation agent in many cell types, causes an upregulation of neurotrophin receptor TrkB and the cyclin kinase inhibitor p21Cip1 at a transcriptional level. Full transcriptional activation of these two genes requires canonical E-box sequences found in the TrkB and p21Cip1 promoters. As reported for other E-box-regulated promoters, ectopic expression of E47 and E12 basic helix-loop-helix (bHLH) proteins enhances RA-dependent expression of TrkB and p21Cip1 , whereas the inhibitory HLH Id2 exerts opposite effects. In addition, ectopic expression of E47 and NeuroD, a neuronal bHLH protein, is able to activate TrkB transcription in the absence of RA. More importantly, we show that E47 and NeuroD proteins bind the TrkB and p21Cip1 promoter sequences in vivo. Since they establish a direct transcriptional link between a cell cycle inhibitor, p21Cip1 , and a neurotrophic receptor, TrkB, bHLH proteins would play an important role in coordinating key events of cell cycle arrest and neuronal differentiation.

scholarly journals Multiple Basic Helix-Loop-Helix Proteins Regulate Expression of the ENO1 Gene of Saccharomyces cerevisiae

2007 ◽  
Vol 6 (5) ◽  
pp. 786-796 ◽  
Author(s):  
Meng Chen ◽  
John M. Lopes
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dominant Negative ◽  
Bhlh Protein ◽  
Dominant Negative Mutant ◽  
Eukaryotic Transcription ◽  
Control Of Gene Expression ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Boxes ◽  
Bhlh Proteins

ABSTRACT The basic helix-loop-helix (bHLH) eukaryotic transcription factors have the ability to form multiple dimer combinations. This property, together with limited DNA-binding specificity for the E box (CANNTG), makes them ideally suited for combinatorial control of gene expression. We tested the ability of all nine Saccharomyces cerevisiae bHLH proteins to regulate the enolase-encoding gene ENO1. ENO1 was known to be activated by the bHLH protein Sgc1p. Here we show that expression of an ENO1-lacZ reporter was also regulated by the other eight bHLH proteins, namely, Ino2p, Ino4p, Cbf1p, Rtg1p, Rtg3p, Pho4p, Hms1p, and Ygr290wp. ENO1-lacZ expression was also repressed by growth in inositol-choline-containing medium. Epistatic analysis and chromatin immunoprecipitation experiments showed that regulation by Sgc1p, Ino2p, Ino4p, and Cbf1p and repression by inositol-choline required three distal E boxes, E1, E2, and E3. The pattern of bHLH binding to the three E boxes and experiments with two dominant-negative mutant alleles of INO4 and INO2 support the model that bHLH dimer selection affects ENO1-lacZ expression. These results support the general model that bHLH proteins can coordinate different biological pathways via multiple mechanisms.

scholarly journals Tumor cell complementation groups based on myogenic potential: evidence for inactivation of loci required for basic helix-loop-helix protein activity.

1996 ◽  
Vol 16 (7) ◽  
pp. 3901-3908 ◽  
Author(s):  
A N Gerber ◽  
S J Tapscott
Keyword(s):  
Protein Function ◽  
Myogenic Differentiation ◽  
Human Tumor ◽  
Cell Types ◽  
Bhlh Protein ◽  
Protein Activity ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Complementation Groups ◽  
Myogenic Program

Basic helix-loop-helix (bHLH) proteins mediate terminal differentiation in many lineages. By using the bHLH protein MyoD, which can dominantly activate the myogenic differentiation program in numerous cell types, we demonstrated that recessive defects in bHLH protein function are present in human tumor lines. In contrast to prior work with primary cell cultures, MyoD did not activate the myogenic program in six of the eight tumor lines we tested. Cell fusions between the MyoD-defective lines and fibroblasts restored MyoD activity, indicating that the deficiency of a gene or factor prevents bHLH protein function in the tumor lines. Fusions between certain pairings of the MyoD-defective lines also restored MyoD activity, allowing the tumor lines to be assigned to complementation groups on the basis of their ability to execute the myogenic program and indicating that multiple mechanisms exist for abrogation of bHLH protein activity. These groups provide a basis for identifying genes critical for bHLH-mediated differentiation and tumor progression by using genetic complementation.

scholarly journals The basic domain of myogenic basic helix-loop-helix (bHLH) proteins is the novel target for direct inhibition by another bHLH protein, Twist.

1997 ◽  
Vol 17 (11) ◽  
pp. 6563-6573 ◽  
Author(s):  
Y Hamamori ◽  
H Y Wu ◽  
V Sartorelli ◽  
L Kedes
Keyword(s):  
Bhlh Protein ◽  
E Proteins ◽  
Basic Domain ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Protein ◽  
Arginine Residues ◽  
Bhlh Proteins

In vertebrates, the basic helix-loop-helix (bHLH) protein Twist may be involved in the negative regulation of cellular determination and in the differentiation of several lineages, including myogenesis, osteogenesis, and neurogenesis. Although it has been shown that mouse twist (M-Twist) (i) sequesters E proteins, thus preventing formation of myogenic E protein-MyoD complexes and (ii) inhibits the MEF2 transcription factor, a cofactor of myogenic bHLH proteins, overexpression of E proteins and MEF2 failed to rescue the inhibitory effects of M-Twist on MyoD. We report here that M-Twist physically interacts with the myogenic bHLH proteins in vitro and in vivo and that this interaction is required for the inhibition of MyoD by M-Twist. In contrast to the conventional HLH-HLH domain interaction formed in the MyoD/E12 heterodimer, this novel type of interaction uses the basic domains of the two proteins. While the MyoD HLH domain without the basic domain failed to interact with M-Twist, a MyoD peptide containing only the basic and helix 1 regions was sufficient to interact with M-Twist, suggesting that the basic domain contacts M-Twist. The replacement of three arginine residues by alanines in the M-Twist basic domain was sufficient to abolish both the binding and inhibition of MyoD by M-Twist, while the domain retained other M-Twist functions such as heterodimerization with an E protein and inhibition of MEF2 transactivation. These findings demonstrate that M-Twist interacts with MyoD through the basic domains, thereby inhibiting MyoD.

Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer

1994 ◽  
Vol 14 (9) ◽  
pp. 6153-6163
Author(s):  
T Genetta ◽  
D Ruezinsky ◽  
T Kadesch
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Zinc Finger Protein ◽  
Immunoglobulin Heavy Chain ◽  
Bhlh Protein ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Box ◽  
Bhlh Proteins

The activity of the immunoglobulin heavy-chain (IgH) enhancer is restricted to B cells, although it binds both B-cell-restricted and ubiquitous transcription factors. Activation of the enhancer in non-B cells upon overexpression of the basic helix-loop-helix (bHLH) protein E2A appears to be mediated not only by the binding of E2A to its cognate E box but also by the resulting displacement of a repressor from that same site. We have identified a "two-handed" zinc finger protein, denoted ZEB, the DNA-binding specificity of which mimics that of the cellular repressor. By employing a derivative E box that binds ZEB but not E2A, we have shown that the repressor is active in B cells and the IgH enhancer is silenced in the absence of binding competition by bHLH proteins. Hence, we propose that a necessary prerequisite of enhancer activity is the B-cell-specific displacement of a ZEB-like repressor by bHLH proteins.

scholarly journals An Examination of the Role of Transcriptional and Posttranscriptional Regulation in Rhabdomyosarcoma

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Alexander J. Hron ◽  
Atsushi Asakura
Keyword(s):  
Skeletal Muscle ◽  
Soft Tissue ◽  
Posttranscriptional Regulation ◽  
Progenitor Cell ◽  
Treatment Options ◽  
Soft Tissue Tumors ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Bhlh Proteins

Rhabdomyosarcoma (RMS) is an aggressive family of soft tissue tumors that most commonly manifests in children. RMS variants express several skeletal muscle markers, suggesting myogenic stem or progenitor cell origin of RMS. In this review, the roles of both recently identified and well-established microRNAs in RMS are discussed and summarized in a succinct, tabulated format. Additionally, the subtypes of RMS are reviewed along with the involvement of basic helix-loop-helix (bHLH) proteins, Pax proteins, and microRNAs in normal and pathologic myogenesis. Finally, the current and potential future treatment options for RMS are outlined.

A novel basic helix-loop-helix protein is expressed in muscle attachment sites of the Drosophila epidermis

1994 ◽  
Vol 14 (6) ◽  
pp. 4145-4154
Author(s):  
P Armand ◽  
A C Knapp ◽  
A J Hirsch ◽  
E F Wieschaus ◽  
M D Cole
Keyword(s):  
Distinct Pattern ◽  
Bhlh Protein ◽  
Muscle Attachment ◽  
Muscle Creatine Kinase ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Attachment Sites ◽  
Bhlh Genes ◽  
Somatic Muscles ◽  
Muscle Attachment Sites

We have found that a novel basic helix-loop-helix (bHLH) protein is expressed almost exclusively in the epidermal attachments sites for the somatic muscles of Drosophila melanogaster. A Drosophila cDNA library was screened with radioactively labeled E12 protein, which can dimerize with many HLH proteins. One clone that emerged from this screen encoded a previously unknown protein of 360 amino acids, named delilah, that contains both basic and HLH domains, similar to a group of cellular transcription factors implicated in cell type determination. Delilah protein formed heterodimers with E12 that bind to the muscle creatine kinase promoter. In situ hybridization with the delilah cDNA localized the expression of the gene to a subset of cells in the epidermis which form a distinct pattern involving both the segmental boundaries and intrasegmental clusters. This pattern was coincident with the known sites of attachment of the somatic muscles to tendon cells in the epidermis. delilah expression persists in snail mutant embryos which lack mesoderm, indicating that expression of the gene was not induced by attachment of the underlying muscles. The similarity of this gene to other bHLH genes suggests that it plays an important role in the differentiation of epidermal cells into muscle attachment sites.

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