Fhit loss in lung preneoplasia: relation to DNA damage response checkpoint activation.
Loss of heterozygosity at the FHIT locus is coincident with activation of DNA damage response checkpoint proteins; thus damage at fragile loci may trigger checkpoint activation. We examined preneoplastic lesions adjacent to non-small cell lung carcinomas for alterations to expression of Fhit and activated checkpoint proteins. Expression scores were analyzed for pair-wise associations and correlations among proteins and type of lesion. Hyperplastic and dysplastic lesions were positive for nuclear gammaH2AX expression; 12/20 dysplastic lesions were negative for Fhit expression. Fhit positive lesions showed expression of most checkpoint proteins examined, while Fhit negative lesions showed absence of expression of Chk1 and phosphoChk1. The results show that loss of expression of Fhit is significantly directly correlated with absence of activated Chk1 in dysplasia, and suggest a connection between loss of Fhit and modulation of checkpoint activity.
Cirombella
Roberto
R
Division of Pathology, II University of Rome La Sapienza, Ospedale Santo Andrea, Rome, Italy.
Montrone
Giuseppe
G
Stoppacciaro
Antonella
A
Giglio
Simona
S
Volinia
Stefano
S
Graziano
Paolo
P
Huebner
Kay
K
Vecchione
Andrea
A
D017766:Acid Anhydride Hydrolases / Q000172:deficiency* / Q000235:genetics; D000071877:Checkpoint Kinase 1; D043283:Chromosome Fragile Sites / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics*; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D000071877:Checkpoint Kinase 1; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011494:Protein Kinases; D000099170:Bis(5'-adenosyl)triphosphatase; C000605867:CHEK1 protein, human