Basic helix-loop-helix proteins bind to TrkB and p21(Cip1) promoters linking differentiation and cell cycle arrest in neuroblastoma cells.
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 p21(Cip1) at a transcriptional level. Full transcriptional activation of these two genes requires canonical E-box sequences found in the TrkB and p21(Cip1) 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 p21(Cip1), 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 p21(Cip1) promoter sequences in vivo. Since they establish a direct transcriptional link between a cell cycle inhibitor, p21(Cip1), and a neurotrophic receptor, TrkB, bHLH proteins would play an important role in coordinating key events of cell cycle arrest and neuronal differentiation.
Liu
Yuhui
Y
Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, 25008 Lleida, Catalunya, Spain.
Encinas
Mario
M
Comella
Joan X
JX
Aldea
Martí
M
Gallego
Carme
C
D000970:Antineoplastic Agents / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D051797:Inhibitor of Differentiation Protein 2; D009419:Nerve Tissue Proteins; D020813:Receptor, trkB; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D014212:Tretinoin; C493956:CDKN1A protein, human; C497450:ID2 protein, human; C544912:TCF7L1 protein, human; C093564:Neurogenic differentiation factor 1