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Basic Helix-Loop-Helix Proteins Bind to TrkB and p21^Cip1 Promoters Linking Differentiation and Cell Cycle Arrest in Neuroblastoma Cells

Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, 25008 Lleida, Catalunya, Spain,¹ Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110²

Received 19 November 2003/ Returned for modification 12 December 2003/ Accepted 11 January 2004

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.

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