Fragile gene product, Fhit, in oxidative and replicative stress responses.
Though the fragile histidine triad gene product, Fhit, was discovered and characterized as a tumor suppressor 13 years ago, its sequence, structure, and cellular location did not provide clues to aid discovery of its mechanisms of suppression. Recently, using chemical cross-linkers and immunoprecipitation, a Fhit protein complex was identified that includes Hsp60 and Hsp10 which may mediate Fhit stability and mitochondrial localization, where Fhit binds and stabilizes ferredoxin reductase (Fdxr); when Fdxr is overexpressed, it can lead to production of reactive oxygen species (ROS) that induce apoptosis. Cancer cells expressing endogenous or exogenous Fhit, when exposed to H(2)O(2), an oxidative stress, produce higher levels of apoptosis-inducing ROS than matched, Fhit-negative cells; the Fhit-negative cancer cells survive, carrying DNA damage. In addition to this mitochondrial function, Fhit-overexpression in cancer cells exposed to replicative stress-inducing agents leads to enhanced caspase 3 activation and apoptosis, due to defective Chk1 activation. Thus, damage to the fragile FHIT locus leads to reduced expression of Fhit protein, and makes a two-pronged contribution to development of preneoplastic clonal expansion: (1) absence or reduction of Fhit leads to reduced expression of Fdxr and reduced ROS-induced apoptosis; (2) cells that escape ROS- or replicative stress-induced apoptosis can carry misrepaired DNA damage. The aberrant DNA damage response checkpoint in Fhit-deficient preneoplasias and cancers may make these lesions targets for inhibitors of proteins such as Parp1 and Chk1 with important roles in checkpoint responses, as observed for BRCA1-deficient cancer cells that also exhibit DNA damage repair deficiencies.
Okumura
Hiroshi
H
Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Ishii
Hideshi
H
Pichiorri
Flavia
F
Croce
Carlo M
CM
Mori
Masaki
M
Huebner
Kay
K
D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004261:DNA Replication; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase