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The Fanconi Anemia Pathway Induces Senescence and Suppresses Tumorigenesis in Vivo
Author(s) -
Park Eunmi,
D'Andrea Alan D
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb400
Subject(s) - fancd2 , fanconi anemia , carcinogenesis , biology , senescence , cancer research , in vivo , dna damage , downregulation and upregulation , cell growth , stathmin , cancer , microbiology and biotechnology , dna repair , phosphorylation , dna , biochemistry , genetics , gene
Fanconi Anemia (FA) is a rare human genetic disease characterized by bone marrow failure, congenital abnormalities, and a high incidence of cancer. The FA pathway regulates the synthesis of monoubiquitinated FANCD2, which is believed to function as a tumor suppressor in vivo. Disruption of the FA pathway, in human FA patients or in FA mouse models, results in an increased incidence of Squamous Cell Carcinomas (SCCs). Consistent with the role of FANCD2 as a tumor suppressor, Fancd2(−/−) murine embryo fibroblasts (MEFs) exhibit decreased RAS‐induced senescence and increased proliferation. We have also recently identified USP1, a cysteine protease which deubiquitinates FANCD2. Interestingly, Usp1(−/−) MEFs have elevated levels of monoubiquitinated Fancd2, and they exhibit increased RAS‐induced senescence and decreased proliferation. Their increase in senescence correlates with their increased cellular expression of TAp63 and p21. Moreover, Usp1(+/−) mice have a decreased incidence of H‐Ras induced squamous cell carcinomas in vivo compared to wild‐type sibling control mice. Taken together, our results indicate that downregulation of USP1 results in increased cellular levels of FANCD2‐Ub and an increased tumor suppressor activity in vivo. Pharmacologic inhibitors of USP1 may therefore function as cancer chemoprevention agents.