@article{christensen_romach_healy_gonzales_anderson_malarkey_corton_fox_cattley_goldsworthy_1999, title={Altered bcl-2 family expression during non-genotoxic hepatocarcinogenesis in mice}, volume={20}, ISSN={["1460-2180"]}, DOI={10.1093/carcin/20.8.1583}, abstractNote={Dysregulation of apoptosis is an important component of multistage hepatocarcinogenesis. Members of the bcl-2 protein family are important in the regulation of apoptosis and their expression is altered in several cancers. The objectives of the present study were to determine whether the expression of members of the bcl-2 protein family are altered in mouse liver during acute treatment with non-genotoxic carcinogens and throughout non-genotoxic hepatocarcinogenesis. Acute treatment of B6C3F1 mice with phenobarbital resulted in increased levels of bcl-2 and decreased levels of bax protein, while acute treatment with WY-14,643 resulted in increased bcl-2 and BAG-1 protein in the liver. Following chronic treatment, altered hepatic foci and adenomas were classified as: small-cell, heterogeneous basophilic lesions (spontaneous or tetrachlorodibenzo-p-dioxin-induced); large-cell, homogeneous basophilic lesions (WY-14,643-induced); acidophilic lesions (phenobarbital- or chlordane-induced). Of the small-cell heterogeneous basophilic lesions, 86% of foci (31/36) and 85% of adenomas (35/41) exhibited increased bcl-2 protein levels compared with surrounding normal hepatocytes, whereas only 12.5% of foci (4/36) and 12% of adenomas (5/41) exhibited increased bcl-X(L) levels. Of the large-cell, homogenous, basophilic lesions, 100% of foci (3/3) and 90% of adenomas (9/10) expressed bcl-2 protein, whereas 100% of foci (3/3) and 80% of adenomas (8/10) exhibited increased bcl-X(L) protein levels compared with surrounding normal hepatocytes. Of the acidophilic lesions, the majority of foci (28/32, 88%) and adenomas (47/50, 94%) expressed increased bcl-X(L), whereas increased bcl-2 was observed in only 12.5% of acidophilic preneoplastic foci (4/32) and 14% of acidophilic adenomas (7/50). Of the carcinomas analyzed, 81% expressed increased bcl-2 (54/67), 78% expressed increased bcl-X(L) (52/67) and 69% expressed increased levels of both bcl-2 and bcl-X(L) (46/67). Collectively, only 8% of preneoplastic foci, 3% of adenomas and 1.5% of carcinomas did not express either bcl-2 or bcl-X(L). These results suggest that regulation of apoptotic proteins is altered during non-genotoxic carcinogenesis in mouse liver. Furthermore, there were both chemical- and lesion-specific aspects of expression of apoptotic proteins during hepatocarcinogenesis in mice.}, number={8}, journal={CARCINOGENESIS}, author={Christensen, JG and Romach, EH and Healy, LN and Gonzales, AJ and Anderson, SP and Malarkey, DE and Corton, JC and Fox, TR and Cattley, RC and Goldsworthy, TL}, year={1999}, month={Aug}, pages={1583–1590} }
 @article{christensen_goldsworthy_cattley_1999, title={Dysregulation of apoptosis by c-myc in transgenic hepatocytes and effects of growth factors and nongenotoxic carcinogens}, volume={25}, number={4}, journal={Molecular Carcinogenesis}, author={Christensen, J. G. and Goldsworthy, T. L. and Cattley, R. C.}, year={1999}, pages={273–284} }
 @article{gonzales_christensen_preston_goldsworthy_tlsty_fox_1998, title={Attenuation of G(1) checkpoint function by the non-genotoxic carcinogen phenobarbital}, volume={19}, ISSN={["0143-3334"]}, DOI={10.1093/carcin/19.7.1173}, abstractNote={Non-genotoxic chemical carcinogens are capable of inducing tumors in rodents without interacting with or directly altering the genetic material. Since a preponderance of evidence suggests that cancer results from the accumulation of genetic alterations, the mechanisms by which many non-genotoxic carcinogens induce genotoxic events remain unclear. The present study investigated whether the mitogenic, non-genotoxic carcinogen phenobarbital (PB) could alter cell-cycle checkpoint controls, thereby indirectly leading to the accumulation of genetic damage. Initial studies involved characterizing cell-cycle checkpoint responses to DNA damage in freshly isolated B6C3F1 mouse hepatocytes. These cells responded to bleomycin-induced DNA damage by arresting in G1 and G2. Cell-cycle arrest was coupled with p53 protein induction; however, p21WAF1 protein levels remained unchanged. Studies that utilized hepatocytes isolated from C57BL p53-/- mice showed that the DNA damage-induced G1 cell-cycle arrest was dependent on p53 function, but cell-cycle arrest in G2 was not affected by loss of p53. PB was able to delay and attenuate the G1 checkpoint response without altering G2 checkpoint function. A reduction in p53 protein, but not transcript levels, was observed in hepatocytes exposed to PB. Additionally, PB delayed and attenuated p53 protein induction during DNA damage, which suggests that changes in the p53 protein may be contributing to the attenuated G1 checkpoint response caused by PB. Altered G1 checkpoint function represents an epigenetic mechanism by which phenobarbital may prevent the detection and repair of DNA damage and indirectly increase the frequency of genotoxic events above that occurring spontaneously. Abrogation of checkpoint controls may, thus, play an important mechanistic role in mitogenic, non-genotoxic chemical carcinogenesis.}, number={7}, journal={CARCINOGENESIS}, author={Gonzales, AJ and Christensen, JG and Preston, RJ and Goldsworthy, TL and Tlsty, TD and Fox, TR}, year={1998}, month={Jul}, pages={1173–1183} }
 @article{christensen_gonzales_cattley_goldsworthy_1998, title={Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens}, volume={9}, number={9}, journal={Cell Growth & Differentiation}, author={Christensen, J. G. and Gonzales, A. J. and Cattley, R. C. and Goldsworthy, T. L.}, year={1998}, pages={815–825} }