Showing papers by "Urban Lendahl published in 2007"

The Tumor Suppressor Gene hCDC4 Is Frequently Mutated in Human T-Cell Acute Lymphoblastic Leukemia with Functional Consequences for Notch Signaling

Abstract: Notch signaling is of crucial importance in normal T-cell development and Notch 1 is frequently mutated in T-cell acute lymphoblastic leukemias (T-ALL), leading to aberrantly high Notch signaling. In this report, we determine whether T-ALL mutations occur not only in Notch1 but also in the F-box protein hCdc4 (Sel-10, Ago, or Fbxw7), a negative regulator of Notch1. We show that the hCDC4 gene is mutated in leukemic cells from more than 30% of patients with pediatric T-ALL and derived cell lines. Most hCDC4 mutations found were missense substitutions at critical arginine residues (Arg(465), Arg(479), and Arg(505)) localized in the substrate-binding region of hCdc4. Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notch1 protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notch1. Furthermore, restoration of wild-type but not mutant hCdc4 in HCT 116 hCDC4-negative cells led to an increased Notch1 ubiquitylation and decreased Notch1 signaling. These results show that hCdc4 mutations interfere with normal Notch1 regulation in vivo. Finally, we found that mutations in hCDC4 and NOTCH1 can occur in the same cancers and that patients carrying hCDC4 and/or NOTCH1 mutations have a favorable overall survival. Collectively, these data show that mutation of hCDC4 is a frequent event in T-ALL and suggest that hCDC4 mutations and gain-of-function mutations in NOTCH1 might synergize in contributing to the development of pediatric T-ALL leukemogenesis.

Modulation of vascular gene expression by hypoxia.

Abstract: PURPOSE OF REVIEW Angiogenesis and inflammation are important features in atherosclerotic plaque destabilization. The transcription factors hypoxia-inducible factor-1alpha and Notch are key regulators of angiogenesis. In addition, hypoxia-inducible factor-1alpha has been linked to regulation of inflammatory processes and innate immunity. This review will document how hypoxia-inducible factor-mediated signaling pathways are initiated in hypoxic cells, and how the hypoxia-inducible factor and Notch-dependent signaling pathways are functionally integrated. RECENT FINDINGS Activation of the hypoxia-inducible factor-mediated signaling events by hypoxia is complex and regulated by a cascade of molecular events that will be reviewed in detail. The activated form of hypoxia-inducible factor enhances Notch-dependent activation of Notch target genes, thereby providing a mechanism by which hypoxia can regulate the differentiation status of a cell. Recent observations implicate the Notch signaling pathway in proper specification of cell identity, position and behavior in a developing blood vessel sprout, and the hypoxia-inducible factor-mediated signaling pathway is critical for induction of expression of vascular endothelial growth factor. SUMMARY Hypoxia-inducible factor and Notch transcription factors represent potentially attractive targets for regulation of angiogenesis and possibly inflammation. In view of the pleiotropic effects of these transcription factors, however, successful targeting of these signaling pathways will require the development of gene specific (and possibly tissue-specific) modulators and extensive validation in relevant model systems.