Notch Dimerization is Required for Leukemogenesis and T-cell Development

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2010 Oct 12

PMID 20935071

Citations 43

Authors

Hudan Liu

Anthony W S Chi

Kelly L Arnett

Mark Y Chiang

Lanwei Xu

Olga Shestova

Hongfang Wang

Yue-Ming Li

Avinash Bhandoola

Jon C Aster

Stephen C Blacklow

Warren S Pear

Affiliations

Soon will be listed here.

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).

Citing Articles

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