The Tumor Suppressor Gene hCDC4 Is Frequently Mutated in Human T-Cell Acute Lymphoblastic Leukemia with Functional Consequences for Notch Signaling
| Autor: | Alena, Malyukova, Takeaki, Dohda, Natalie, von der Lehr, Shahab, Akhoondi, Shahab, Akhondi, Martin, Corcoran, Mats, Heyman, Charles, Spruck, Dan, Grandér, Urban, Lendahl, Olle, Sangfelt |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research F-Box-WD Repeat-Containing Protein 7 Tumor suppressor gene Ubiquitin-Protein Ligases T cell Blotting Western DNA Mutational Analysis Mutant Notch signaling pathway Cell Cycle Proteins Biology Polymerase Chain Reaction hemic and lymphatic diseases medicine Humans Leukemia-Lymphoma Adult T-Cell Missense mutation Receptor Notch1 Child Gene Notch 1 Polymorphism Single-Stranded Conformational Base Sequence F-Box Proteins medicine.anatomical_structure Oncology Mutation embryonic structures cardiovascular system Cancer research Female sense organs biological phenomena cell phenomena and immunity Signal transduction Signal Transduction |
| Zdroj: | Cancer Research. 67:5611-5616 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-06-4381 |
| Popis: | 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 (Arg465, Arg479, and Arg505) 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. [Cancer Res 2007;67(12):5611–6] |
| Databáze: | OpenAIRE |
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