Influence of poly(ADP ribose) polymerase depletion on promotion of liver carcinogenesis.
In previous studies we demonstrated that liver poly(ADP ribose) polymerase (pADPRP) activity was lost in animals exposed to N-2-acetylaminofluorene (2AAF) according to the Teebor and Becker experimental model (Cancer Res 31:1-3, 1971). In addition, we used the resistant hepatocyte model of Solt and Farber (Nature 263:702-703, 1976) to further investigate pADPRP activity during the multistep process of liver carcinogenesis. A marked depletion of the catalytic protein was evidenced after 2AAF exposure, confirming previous results and indicating a specific effect of 2AAF on this nuclear enzyme that controls conformational changes of chromatin and regulates several catalytic activities in the nucleus. The levels of pADPRP mRNA, measured by northern blot analysis using both experimental models, indicate that the enzyme depletion is not due to a loss of transcript. Moreover, these data indicate that pADPRP depletion, caused by 2AAF, was also maintained during liver compensatory growth, which is known to induce a rapid and marked increase in pADPRP activity and protein level. Treatment of 2AAF-exposed animals with N-acetyl-L-cysteine not only efficiently protected against DNA damage, but also prevented a rapid depletion of the catalytic protein. Interestingly, these data indicate that the marked loss of liver pADPRP occurred during the promotion step induced by 2AAF feeding and that this loss was observed using different models for experimental hepatocarcinogenesis. This phenomenon can be ascribed to a highly defective transcript that cannot be correctly translated into the specific protein or to a rapid degradation of the translated protein.
Cesarone
C F
CF
Istituto di Fisiologia Generale, Facoltá di Scienze, Genova, Italy.
Suzuki
H
H
Scovassi
A I
AI
Scarabelli
L
L
Izzo
R
R
Giannoni
P
P
Mariani
C
C
Miwa
M
M
Orunesu
M
M
Bertazzoni
U
U
D015073:2-Acetylaminofluorene; D000818:Animals; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D012333:RNA, Messenger; D015073:2-Acetylaminofluorene; D011065:Poly(ADP-ribose) Polymerases