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 Haneline, Attilio Orazi, Hal Broxmeyer, Suk-Hee Lee, D. Clapp

Research output: Contribution to journalArticle

50 Citations (Scopus)

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

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Fanconi Anemia
Tumors
Carcinogenesis
Apoptosis
Ionizing radiation
Automatic teller machines
Bone
Tumor Necrosis Factor-alpha
Genes
Neoplasms
BRCA2 Protein
Defects
Bone Neoplasms
Myeloid Leukemia
Genomic Instability
Myeloid Cells
Ionizing Radiation
Proteins
DNA Damage
Bone Marrow

ASJC Scopus subject areas

  • Hematology

Cite this

Freie, B., Li, X., Ciccone, S. L. M., Nawa, K., Cooper, S., Vogelweid, C., ... Clapp, D. (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

Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. / Freie, Brian; Li, Xiaxin; Ciccone, Samantha L M; Nawa, Kathy; Cooper, Scott; Vogelweid, Catherine; Schantz, Laurel; Haneline, Laura; Orazi, Attilio; Broxmeyer, Hal; Lee, Suk-Hee; Clapp, D.

In: Blood, Vol. 102, No. 12, 01.12.2003, p. 4146-4152.

Research output: Contribution to journalArticle

Freie, B, Li, X, Ciccone, SLM, Nawa, K, Cooper, S, Vogelweid, C, Schantz, L, Haneline, L, Orazi, A, Broxmeyer, H, Lee, S-H & Clapp, D 2003, 'Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis', Blood, vol. 102, no. 12, pp. 4146-4152. https://doi.org/10.1182/blood-2003-03-0971
Freie B, Li X, Ciccone SLM, Nawa K, Cooper S, Vogelweid C et al. Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. Blood. 2003 Dec 1;102(12):4146-4152. https://doi.org/10.1182/blood-2003-03-0971
Freie, Brian ; Li, Xiaxin ; Ciccone, Samantha L M ; Nawa, Kathy ; Cooper, Scott ; Vogelweid, Catherine ; Schantz, Laurel ; Haneline, Laura ; Orazi, Attilio ; Broxmeyer, Hal ; Lee, Suk-Hee ; Clapp, D. / Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. In: Blood. 2003 ; Vol. 102, No. 12. pp. 4146-4152.
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