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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-03-0971.
Submitted March 31, 2003
Accepted June 23, 2003
Fanconi Anemia type C and p53 cooperate in apoptosis and tumorigenesis
Brian W 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, and D Wade Clapp*
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Laboratory Animal Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA; Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA
* Corresponding author; email: dclapp{at}iupui.edu.
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. Though FA patients are highly predisposed to the development of myeloid leukemia and solid tumors, the alterations in biochemical pathways responsible for the progression of tumorigenesis in FA 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  -induced apoptosis in Fancc-/- myeloid cells. Further, while 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 FA patients 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.
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