| Abstract: |
Notch signaling regulates myriad cellular functions by activating transcription, yet how Notch selectively activates different transcriptional targets is poorly understood. The core Notch transcriptional activation complex can bind DNA as a monomer, but it can also dimerize on DNA-binding sites that are properly oriented and spaced. However, the significance of Notch dimerization is unknown. Here, we show that dimeric Notch transcriptional complexes are required for T-cell maturation and leukemic transformation but are dispensable for T-cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization result from the differential sensitivity of specific Notch target genes. In particular, c-Myc and pre-T-cell antigen receptor α (Ptcra) are dimerization-dependent targets, whereas Hey1 and CD25 are not. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Consequently, it may be possible to develop a new class of Notch inhibitors that selectively block outcomes that depend on Notch dimerization (e.g., leukemogenesis). © 2010 by Cold Spring Harbor Laboratory Press. |
| Keywords: |
signal transduction; protein expression; leukemia; human cell; nonhuman; flow cytometry; sensitivity analysis; cell proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; animals; mice; gene; cells, cultured; cell growth; cell maturation; animal experiment; notch receptor; cell fate; receptor, notch1; transcription, genetic; cell line, tumor; mice, inbred c57bl; protein multimerization; reverse transcriptase polymerase chain reaction; membrane glycoproteins; cell transformation; leukemia cell; leukemogenesis; transcription; base sequence; binding site; models, molecular; dimerization; protein structure, tertiary; binding sites; sequence homology, nucleic acid; c-myc; oncogene c myc; proto-oncogene proteins c-myc; lymphocyte; receptors, antigen, t-cell, alpha-beta; interleukin 2 receptor alpha; notch1 receptor; precursor t-cell lymphoblastic leukemia-lymphoma; notch; t-all; hey1 gene; ptalpha gene; ptca gene
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