Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis.
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 alpha-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.
Freie
Brian
B
Cancer Research Institute, 1044 W Walnut St, R4/408, Indianapolis, IN 46202, USA.
Li
Xiaxin
X
Ciccone
Samantha L M
SL
Nawa
Kathy
K
Cooper
Scott
S
Vogelweid
Catherine
C
Schantz
Laurel
L
Haneline
Laura S
LS
Orazi
Attilio
A
Broxmeyer
Hal E
HE
Lee
Suk-Hee
SH
Clapp
D Wade
DW
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000166:cytology; D005199:Fanconi Anemia / Q000150:complications / Q000473:pathology*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005347:Fibroblasts / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D040582:Inheritance Patterns; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011839:Radiation, Ionizing; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53