Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis

Brian Freie, Xiaxin Li, Samantha L.M. Ciccone, Kathy Nawa, Scott Cooper, Catherine Vogelweid, Laurel Schantz, Laura S. Haneline, Attilio Orazi, Hal E. Broxmeyer, Suk Hee Lee, D. Wade Clapp

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Fanconi anemia (FA) is a recessive genomic instability syndrome characterized by developmental defects, progressive bone marrow failure, and cancer. FA is genetically heterogeneous, however; the proteins encoded by different FA loci interact functionally with each other and with the BRCA1, BRCA2, and ATM gene products. Although patients with FA are highly predisposed to the development of myeloid leukemia and solid tumors, the alterations in biochemical pathways responsible for the progression of tumorigenesis in these patients remain unknown. FA cells are hypersensitive to a range of genotoxic and cellular stresses that activate signaling pathways mediating apoptosis. Here we show that ionizing radiation (IR) induces modestly elevated levels of p53 in cells from FA type C (Fancc) mutant mice and that inactivation of Trp53 rescues tumor necrosis factor α-induced apoptosis in myeloid cells from Fancc-/- mice. Further, whereas Fancc-/- mice failed to form hematopoietic or solid malignancies, mice mutant at both Fancc and Trp53 developed tumors more rapidly than mice mutant at Trp53 alone. This shortened latency was associated with the appearance of tumor types that are found in patients with FA but not in mice mutant at Trp53 only. Collectively, these data demonstrate that p53 and Fancc interact functionally to regulate apoptosis and tumorigenesis in Fancc-deficient cells.

Original languageEnglish (US)
Pages (from-to)4146-4152
Number of pages7
JournalBlood
Volume102
Issue number12
DOIs
StatePublished - Dec 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Freie, B., Li, X., Ciccone, S. L. M., Nawa, K., Cooper, S., Vogelweid, C., Schantz, L., Haneline, L. S., Orazi, A., Broxmeyer, H. E., Lee, S. H., & Clapp, D. W. (2003). Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. Blood, 102(12), 4146-4152. https://doi.org/10.1182/blood-2003-03-0971