This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hollander, M. C. Articles by Fornace, A. J. Search for Related Content PubMed PubMed Citation Articles by Hollander, M. C. Articles by Fornace, A. J., Jr.

Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

NIH, National Cancer Institute (NCI), Division of Basic Science, Bethesda, Maryland 20892 [M. C. H., O. K., J. M. S., K. E. K., A. D. P., A. J. F.], and Science Applications International Corp., NCI-Frederick, Frederick, Maryland 21702 [D. C. H.]

	ABSTRACT

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Mice lacking the Gadd45a gene are susceptible to ionizing radiation-induced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10–14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45a-null mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV- and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

	INTRODUCTION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Gadd45a is a M_r 21,000 protein that has been linked to many important cellular processes such as DNA repair, chromatin accessibility, cell cycle checkpoints, and genome stability (1, 2, 3, 4, 5) . GGR² , a subtype of NER was decreased in mouse embryo fibroblast cells lacking Gadd45a, whereas TCR was unchanged (2) . In vitro assays have shown that addition of Gadd45a can prevent assembly of histones onto DNA and can specifically bind to UV-induced lesions in nucleosome complexes (3) . It was, therefore, proposed that Gadd45a may enhance DNA repair by allowing accessibility of repair complexes to damaged DNA.

In the human genetic diseases XP and CS, one of many genes involved in NER, which confers sensitivity of these individuals to UV radiation-induced carcinogenesis and/or sunburn, is mutated or missing (reviewed in Ref. 6 ). Mouse models of XP have been generated that show this same predisposition to UV-induced carcinogenesis as well as carcinogenesis by other agents that produce damage repaired by NER (7 , 8) . The NER defects in XP often involve the GGR subpathway and are associated with increased tumors. In contrast, a defect in TCR, such as in CS, is associated with sun sensitivity, yet no increased carcinogenesis has been observed (9) . GGR is defective in Gadd45a-null cells, and therefore, increased carcinogenesis by agents producing damage repaired by NER was anticipated in mice lacking this gene.

Gadd45a-null mice were shown to have a decreased latency for IR-induced tumors (5) . However, IR produces predominantly DNA strand breaks and base damage that are not repaired by NER. Like XPA and XPC-null mice, most Gadd45a-null mice appear normal and do not show a significant increase in spontaneous tumors. However, laboratory mice live in very controlled environments in the absence of UV radiation or carcinogens. It is likely that these genes are not required to prevent spontaneous tumors when there is no exogenous damage to the DNA. In the presence of damage, lack of any one of many DNA repair genes could lead to increased mutagenesis and consequently carcinogenesis. To determine the effect of Gadd45a deletion on tumorigenesis by an agent whose damage is repaired by NER, young mice were injected i.p. with DMBA and monitored for tumors. There was a small increase in tumor-induced mortality and prevalence of tumors in Gadd45a-null mice compared with wt mice. However, there were far more Gadd45a-null mice with multiple tumors and a dramatic increase in vascular, ovarian, and hepatocellular tumors.

	MATERIALS AND METHODS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Animals.
Mice were housed in Plexiglas cages and given autoclaved NIH 31 diet and water ad libitum. NIH is an Association for Assessment and Accreditation of Laboratory Animal Care-accredited animal facility, and all experiments were done under an approved NCI animal study protocol.

Mice were treated at 10–14 days of age with a single i.p. injection of DMBA in corn oil. The study consisted of 11 female and 15 male Gadd45a-null mice and 11 female and 13 male wt mice. Animals exhibiting obvious tumors or who were moribund, cachectic, or nonresponsive were killed for necropsy, and at 17 months after DMBA injection, surviving animals were killed for necropsy. Tumors and abnormal tissue were taken for histopathological analysis. Tumor and tissue sections were collected, stained with H&E, and evaluated by a board-certified veterinary pathologist.

DNA Repair and Mutation Assays.
Splenic lymphocytes were isolated from spleens of 4- to 6-week-old mice by disruption between two sterile glass slides and grown as previously described (5) . The relative percentage of 6-4 photoproducts in total genomic DNA was determined using an ELISA as previously described (10 , 11) . Briefly, splenic cells in culture were UV (254 nm) irradiated (10 J/m²), and DNA was prepared 3 to 24 h later. Genomic DNA was extracted using a Blood Kit (Qiagen) according to the manufacturer‘s recommendations. Polyvinyl chloride flat-bottomed microtiter plates precoated with 1% protamine sulfate (Sigma) were incubated with 300 ng of DNA in PBS at 37°C for 20 h. After drying, the plates were washed five times with PBS containing 0.05% Tween (PBST). The plates were blocked with 2% fetal bovine serum in PBS for 30 min at 37°C. After five washings with PBST, the plates were incubated with 64M-2 (11) anti-(6-4) photoproduct antibodies (in quadruplicate) diluted 1:1000 in PBS. Another five PBST washings were followed by two consecutive incubations (30 min, 37°C) with goat antimouse IgG F(ab')₂ fragment conjugated with biotin (1:2000 dilution in PBS; Zymed) and then with streptavidin-peroxidase conjugate (1:10000 dilution in PBS; Zymed). Finally, after five PBST washings and one citrate-phosphate buffer (pH 5.0) washing, 100 µl of substrate solution (0.04% o-phenylene diamine and 0.0075% H₂O₂ in citrate-phosphate buffer) were added to each well and incubated for 30 min at 37°C. Reactions were stopped with 50 µl 2 M H₂SO₄. The absorbance at 490 nm was measured using an E-max microplate reader (Molecular Devices).

Gadd45a-null mice were crossed into the BigBlue strain of mice, which harbor a shuttle vector that can be used for mutation detection. Six-week-old mice that carried the integration and were either wt or null for Gadd45a were injected i.p. with 20 nmol/g body weight DMBA, and tissues were harvested for DNA isolation 7 days later. Genomic DNA was prepared using the RecoverEase DNA isolation kit, and bacteriophage were packaged using Transpack packaging extract (Stratagene). At least 2 x 10⁴ plaques were screened for cII mutations, according to the manufacturer‘s instructions in the cII Mutation Assay Detection Kit (Stratagene).

RNA Analysis.
For RNA isolation, 6-week-old mice were injected i.p. with 20 nmol of DMBA/g body weight, and tissues were harvested 4 h later. Tissues were immediately homogenized in RNAzol (Life Technologies), and RNA was prepared as directed by the manufacturer. RNA was dot-blotted onto nylon membranes (Nytran; Schleicher & Schull). cDNA probes were labeled with [³²P]dCTP using Prime-It random primer labeling (Stratagene). Gadd45a RNA was normalized to poly(A) content, which was estimated by hybridization to a labeled polyuridylic acid probe (12 , 13) . Radioactivity for RNA dot blots was counted on a PhosphorImager (Molecular Dynamics).

	RESULTS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Because Gadd45a is involved in NER, it was expected that there would be decreased DNA repair leading to increased DMBA-induced mutations in Gadd45a-null animals, resulting in more tumors. Because of the involvement of Gadd45a in cell cycle checkpoints, growth control, and genome stability, there was also the possibility that these features of the Gadd45a-null phenotype could contribute to decreased latency and increased incidence. The dose of DMBA used was expected to produce tumors in wt animals so that tumor types, incidence rates, and latency could be compared between Gadd45a-null and wt mice. At 16 months posttreatment, there was a slight increase in the incidence of deaths in the Gadd45a-null mice (Fig. 1) , primarily attributable to killing of moribund Gadd45a-null males. For males, 6 (40%) of 15 Gadd45a-null died early compared with 2 (15%) of 13 wt, whereas in the females, 3 (27%) of 11 Gadd45a-null died early compared with 4 (36%) of 11 wt. Only one early killing each in the wt males and Gadd45a-null males and two early sacrifices in the Gadd45a-null females were not attributable to neoplasia. All surviving mice were necropsied at 17 months.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Survival of Gadd45a-null and wt mice after DMBA treatment. Mice were injected at 10–14 days old with 20 nmol/g body weight i.p. DMBA. Animals were followed for up to 17 months at which time all surviving animals were necropsied. Mice with obvious tumors or ill health were killed for necropsy, and most mice that died before 17 months were found to have tumors.

View larger version (39K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. DMBA-induced tumor incidence in Gadd45a-null and wt mice. Animals are the same as those in Fig. 1 . Data include tumors from animals that died during the study as well as animals killed at 17 months at the end of the study. Tumors were examined and typed by a board-certified veterinary pathologist. *, significantly different (P < 0.03) by t test and one-way ANOVA.

Gadd45a RNA is increased in cell cultures and in vivo after treatment with a variety of agents that damage DNA. This increase might provide a protective function because Gadd45a is involved, either directly or indirectly, in NER, the DNA repair pathway that repairs bulky lesions such as those produced by DMBA. Wt mice were injected with the same dose of DMBA that was used for carcinogenesis, and Gadd45a RNA levels were measured after 4 h, the time when Gadd45a RNA levels are often maximal after treatment with DNA-damaging agents. From 5- to >20-fold induction was seen in various tissues (Fig. 3) . The highest induction was seen in the liver, which might be expected because this is probably the major organ that metabolizes DMBA. Induction was seen both in organs in which tumors were more prevalent in Gadd45a-null mice as well as those in which there was no increase in tumors in Gadd45a-null mice.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Gadd45a RNA levels after injection with 20 nmol/g body weight i.p. DMBA. Female mice were injected at 6 weeks of age, and tissues were harvested for RNA 4 h after treatment, as described in "Materials and Methods." Results are average from three untreated and three treated animals.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. GGR of 6-4 photoproducts in Gadd45a-null and wt primary mouse splenic lymphocytes. Results are representative of two experiments (two wt and two Gadd45a-null mice), which showed decreased repair in Gadd45a-null compared with wt lymphocytes.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Increased persistent DMBA-induced mutations in liver of Gadd45a-null mice. Male and female BigBlue transgenic mice of the indicated genotypes were treated as in Fig. 3 , and liver DNA was isolated 7 days after treatment. Mutations in the cII gene were detected, as described in "Materials and Methods."

	DISCUSSION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

DMBA produces bulky DNA adducts that are repaired via NER. Because NER is defective in cells derived from Gadd45a-null mice, it was expected that unrepaired DMBA mutations would lead to more tumors in these mice. Gadd45a-null mice did indeed develop more DMBA-induced tumors than wt mice (Fig. 2) . This increase in tumors was associated with decreased NER in splenic lymphocytes (Fig. 4) , and an increase in DMBA-induced mutations was found in Gadd45a-null liver, consistent with decreased repair (Fig. 5) . Therefore, a mechanism for increased tumorigenesis in these mice can be ascertained by which critical mutations lead to tumor formation.

XP and CS are two rare human photosensitive disorders (9) . Nine different genes were found to be responsible for various forms of these diseases, all of which are involved in NER. XPA, XPB, XPD, XPF, and XPG are all defective in both subpathways of NER, GGR, and TCR. Only XPC and XPE are involved solely in GGR. In contrast, CSA and CSB are involved solely in TCR. In animal models, GGR is the major determinant of UV-induced skin cancer, whereas TCR is the major determinant of sunburn (16) . This is consistent with the relative lack of tumor formation in CS patients, whose cells are defective only in TCR. Like XPC, Gadd45a is not required for efficient TCR but is essential for maximal GGR.

Other similarities exist between XPC, XPE, and Gadd45a. All three have affinity for UV-induced DNA lesions in the context of chromatin and have postulated roles in lesion accessibility. XPC is the earliest factor involved in the initial recognition of damage in reconstituted in vitro assays. XPC changes the DNA conformation around lesions, and this has been suggested to facilitate binding of other NER proteins to the lesion (17) . Likewise, Gadd45a can bind to damaged DNA in chromatin, the natural state of DNA in the cell. In vitro experiments suggest that Gadd45a may alter chromatin structure, perhaps allowing access to XPC or other repair proteins in vivo. XPE forms a complex in vivo that tightly associates with chromatin after DNA damage, suggesting that, like Gadd45a, it is also involved in recognition of chromatinized DNA damage (18) . In addition to established or potential roles in damage recognition, XPC, XPE, and Gadd45a are all activated by the tumor suppressor p53 (19 , 20) .³ p53 regulation of these three genes, which may have similar functions in damage recognition, supports the involvement of p53 in the NER pathway.

XPA-deficient mice are sensitive to UV-induced skin tumors as well as to benzo(a)pyrene-induced internal tumors (7 , 21) . Like Gadd45a-null mice, none of these mouse models for human NER deficiency syndromes show high levels of spontaneous tumors. Gadd45a deletion in mice, therefore, resembles mouse models of XP. Mouse models of XP, however, have generally less severe phenotypes than their human counterparts, which also show neurological symptoms (9) . This is not surprising because GGR in mice is much less robust than in humans. Human mutations in Gadd45a have not been found in human tumor cell lines (Ref. 22 and data not shown), although few tumor types have been examined. A human inactivation of Gadd45a would be expected to confer increased carcinogeninduced tumorigenesis, perhaps similar to XP.

DMBA-treated Gadd45a-null mice had a dramatically higher multiplicity of tumors than did wt mice, with many developing multiple different malignant tumors. The reason for this increase in tumorigenicity and malignancy may result from the growth and transformation properties observed for Gadd45-null cells in culture. Gadd45a-null MEF grow more rapidly and are immortal. These cells are transformed by a single oncogene (activated ras) and exhibit genomic instability (5) . Therefore, in a multistage model of carcinogenesis, Gadd45a-null cells may already have compromised growth control mechanisms and hence may be even more susceptible to malignant transformation by additional cellular events.

	ACKNOWLEDGMENTS

 
We thank Dr. Toshio Mori for the kind gift of anti-(6-4) photoproduct monoclonal antibody.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at NIH, Building 37, Room 6144, Bethesda, MD 20892. Phone: (301) 402-0745; Fax: (301) 480-2514; E-mail: ch96b{at}nih.gov

² The abbreviations used are: GGR, global genomic repair; NER, nucleotide excision repair; TCR, transcription-coupled repair; CS, Cockayne‘s syndrome; XP, xeroderma pigmentosum; IR, ionizing radiation; DMBA, dimethylbenzanthracene; wt, wild type.

³ Sally Amundson, personal communication.

Received 10/27/00. Accepted 1/16/01.

	REFERENCES

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Smith M. L., Chen I. T., Zhan Q., Bae I., Chen C. Y., Gilmer T. M., Kastan M. B., O‘Connor P. M., Fornace A. J., Jr. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen [see comments]. Science (Washington DC), 266: 1376-1380, 1994.[Abstract/Free Full Text]
2. Smith M. L., Ford J. M., Hollander M. C., Bortnick R. A., Amundson S. A., Seo Y. R., Deng C. X., Hanawalt P. C., Fornace A. J., Jr. p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol. Cell. Biol., 20: 3705-3714, 2000.[Abstract/Free Full Text]
3. Carrier F., Georgel P. T., Pourquier P., Blake M., Kontny H. U., Antinore M. J., Gariboldi M., Myers T. G., Weinstein J. N., Pommier Y., Fornace A. J., Jr. Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol. Cell. Biol., 19: 1673-1685, 1999.[Abstract/Free Full Text]
4. Zhan Q., Antinore M. J., Wang X. W., Carrier F., Smith M. L., Harris C. C., Fornace A. J., Jr. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene, 18: 2892-2900, 1999.[Medline]
5. Hollander M. C., Sheikh M. S., Bulavin D. V., Lundgren K., Augeri-Henmueller L., Shehee R., Molinaro T. A., Kim K. E., Tolosa E., Ashwell J. D., Rosenberg M. P., Zhan Q., Fernandez-Salguero P. M., Morgan W. F., Deng C. X., Fornace A. J., Jr. Genomic instability in Gadd45a-deficient mice. Nat. Genet., 23: 176-184, 1999.[Medline]
6. de Boer J., Hoeijmakers J. H. Nucleotide excision repair and human syndromes. Carcinogenesis (Lond.), 21: 453-460, 2000.[Abstract/Free Full Text]
7. de Vries A., van Oostrom C. T., Hofhuis F. M., Dortant P. M., Berg R. J., de Gruijl F. R., Wester P. W., van Kreijl C. F., Capel P. J., van Steeg H., et al Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature (Lond.), 377: 169-173, 1995.[Medline]
8. Friedberg E. C., Bond J. P., Burns D. K., Cheo D. L., Greenblatt M. S., Meira L. B., Nahari D., Reis A. M. Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Mutat. Res., 459: 99-108, 2000.[Medline]
9. van Steeg H., Kraemer K. H. Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Mol. Med. Today, 5: 86-94, 1999.[Medline]
10. Matsunaga T., Mori T., Nikaido O. Base sequence specificity of a monoclonal antibody binding to (6-4) photoproducts. Mutat. Res., 235: 187-194, 1990.[Medline]
11. Mori T., Nakane M., Hattori T., Matsunaga T., Ihara M., Nikaido O. Simultaneous establishment of monoclonal antibodies specific for either cyclobutane pyrimidine dimer or (6-4) photoproduct from the same mouse immunized with ultraviolet-irradiated DNA. Photochem. Photobiol., 54: 225-232, 1991.[Medline]
12. Hollander M. C., Fornace A. J., Jr. Estimation of relative mRNA content by filter hybridization to a polythymidylate probe. Biotechniques, 9: 174-179, 1990.[Medline]
13. Koch-Paiz C. A., Momenan R., Amundson S. A., Lamoreaux R., Fornace A. J., Jr. Estimation of relative mRNA content by filter hybridization to a polyuridylic probe. Biotechniques, 29: 706-714, 2000.[Medline]
14. Buermeyer A. B., Deschenes S. M., Baker S. M., Liskay R. M. Mammalian DNA mismatch repair. Annu. Rev. Genet., 33: 533-564, 1999.[Medline]
15. Ljungman M., Zhang F. Blockage of RNA polymerase as a possible trigger for u.v. light-induced apoptosis. Oncogene, 13: 823-831, 1996.[Medline]
16. Berg R. J., Rebel H., van der Horst G. T., van Kranen H. J., Mullenders L. H., van Vloten W. A., de Gruijl F. R. Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice. Cancer Res., 60: 2858-2863, 2000.[Abstract/Free Full Text]
17. van der Spek P. J., Eker A., Rademakers S., Visser C., Sugasawa K., Masutani C., Hanaoka F., Bootsma D., Hoeijmakers J. H. XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. Nucleic Acids Res., 24: 2551-2559, 1996.[Abstract/Free Full Text]
18. Otrin V. R., McLenigan M., Takao M., Levine A. S., Protic M. Translocation of a UV-damaged DNA binding protein into a tight association with chromatin after treatment of mammalian cells with UV light. J. Cell Sci., 110 (Pt 10): 1159-1168, 1997.[Abstract]
19. Kastan M. B., Zhan Q., el-Deiry W. S., Carrier F., Jacks T., Walsh W. V., Plunkett B. S., Vogelstein B., Fornace A. J., Jr. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell, 71: 587-597, 1992.[Medline]
20. Hwang B. J., Ford J. M., Hanawalt P. C., Chu G. Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc. Natl. Acad. Sci. USA, 96: 424-428, 1999.[Abstract/Free Full Text]
21. Ide F., Iida N., Nakatsuru Y., Oda H., Tanaka K., Ishikawa T. Mice deficient in the nucleotide excision repair gene XPA have elevated sensitivity to benzo[a]pyrene induction of lung tumors. Carcinogenesis (Lond.), 21: 1263-1265, 2000.[Abstract/Free Full Text]
22. Blaszyk H., Hartmann A., Sommer S. S., Kovach J. S. A polymorphism but no mutations in the GADD45 gene in breast cancers. Hum. Genet., 97: 543-547, 1996.[Medline]

This article has been cited by other articles:

				R. S. M. Shih, S. H. K. Wong, N. W. Schoene, and K. Y. Lei Suppression of Gadd45 Alleviates the G2/M Blockage and the Enhanced Phosphorylation of p53 and p38 in Zinc Supplemented Normal Human Bronchial Epithelial Cells Experimental Biology and Medicine, March 1, 2008; 233(3): 317 - 327. [Abstract] [Full Text] [PDF]

				W. O. Ward, D. A. Delker, S. D. Hester, S.-F. Thai, D. C. Wolf, J. W. Allen, and S. Nesnow Transcriptional Profiles in Liver from Mice Treated with Hepatotumorigenic and Nonhepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil Toxicol Pathol, December 1, 2006; 34(7): 863 - 878. [Abstract] [Full Text] [PDF]

				D. Zhang, L. Song, J. Li, K. Wu, and C. Huang Coordination of JNK1 and JNK2 Is Critical for GADD45{alpha} Induction and Its Mediated Cell Apoptosis in Arsenite Responses J. Biol. Chem., November 10, 2006; 281(45): 34113 - 34123. [Abstract] [Full Text] [PDF]

				Q. Cai, N. I. Dmitrieva, J. D. Ferraris, L. F. Michea, J. M. Salvador, M. C. Hollander, A. J. Fornace Jr., R. A. Fenton, and M. B. Burg Effects of expression of p53 and Gadd45 on osmotic tolerance of renal inner medullary cells Am J Physiol Renal Physiol, August 1, 2006; 291(2): F341 - F349. [Abstract] [Full Text] [PDF]

				M. C. Hollander, R. T. Philburn, A. D. Patterson, S. Velasco-Miguel, E. C. Friedberg, R. I. Linnoila, and A. J. Fornace Jr. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis PNAS, September 13, 2005; 102(37): 13200 - 13205. [Abstract] [Full Text] [PDF]

				J. M. Roper, S. C. Gehen, R. J. Staversky, M. C. Hollander, A. J. Fornace Jr., and M. A. O'Reilly Loss of Gadd45a does not modify the pulmonary response to oxidative stress Am J Physiol Lung Cell Mol Physiol, April 1, 2005; 288(4): L663 - L671. [Abstract] [Full Text] [PDF]

				H. Gao, S. Jin, Y. Song, M. Fu, M. Wang, Z. Liu, M. Wu, and Q. Zhan B23 Regulates GADD45a Nuclear Translocation and Contributes to GADD45a-induced Cell Cycle G2-M Arrest J. Biol. Chem., March 25, 2005; 280(12): 10988 - 10996. [Abstract] [Full Text] [PDF]

				I. Zurer, L. J. Hofseth, Y. Cohen, M. Xu-Welliver, S. P. Hussain, C. C. Harris, and V. Rotter The role of p53 in base excision repair following genotoxic stress Carcinogenesis, January 1, 2004; 25(1): 11 - 19. [Abstract] [Full Text] [PDF]

				F. Jiang, P. Li, A. J. Fornace Jr., S. V. Nicosia, and W. Bai G2/M Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through the Induction of GADD45 via an Exonic Enhancer J. Biol. Chem., November 28, 2003; 278(48): 48030 - 48040. [Abstract] [Full Text] [PDF]

				R. K. Vinson and B. F. Hales Genotoxic Stress Response Gene Expression in the Mid-Organogenesis Rat Conceptus Toxicol. Sci., July 1, 2003; 74(1): 157 - 164. [Abstract] [Full Text] [PDF]

				D. V. Bulavin, O. Kovalsky, M. C. Hollander, and A. J. Fornace Jr. Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a Mol. Cell. Biol., June 1, 2003; 23(11): 3859 - 3871. [Abstract] [Full Text] [PDF]

				W. Qiu, D. David, B. Zhou, P. G. Chu, B. Zhang, M. Wu, J. Xiao, T. Han, Z. Zhu, T. Wang, et al. Down-Regulation of Growth Arrest DNA Damage-Inducible Gene 45{beta} Expression Is Associated with Human Hepatocellular Carcinoma Am. J. Pathol., June 1, 2003; 162(6): 1961 - 1974. [Abstract] [Full Text] [PDF]

				M. S. Turker Autosomal mutation in somatic cells of the mouse Mutagenesis, January 1, 2003; 18(1): 1 - 6. [Abstract] [Full Text] [PDF]

				J. Hildesheim, D. V. Bulavin, M. R. Anver, W. G. Alvord, M. C. Hollander, L. Vardanian, and A. J. Fornace Jr. Gadd45a Protects against UV Irradiation-induced Skin Tumors, and Promotes Apoptosis and Stress Signaling via MAPK and p53 Cancer Res., December 15, 2002; 62(24): 7305 - 7315. [Abstract] [Full Text] [PDF]

				Y. R. Seo, M. R. Kelley, and M. L. Smith From the Cover: Selenomethionine regulation of p53 by a ref1-dependent redox mechanism PNAS, October 29, 2002; 99(22): 14548 - 14553. [Abstract] [Full Text] [PDF]

				J. Hildesheim and A. J. Fornace Jr. Gadd45a: An Elusive Yet Attractive Candidate Gene in Pancreatic Cancer : Commentary re: K. Yamasawa et al., Clinicopathological Significance of Abnormalities in Gadd45 Expression and Its Relationship to p53 in Human Pancreatic Cancer. Clin. Cancer Res., 8: 2563-2569, 2002 Clin. Cancer Res., August 1, 2002; 8(8): 2475 - 2479. [Full Text] [PDF]

				M. L. Smith and Y. R. Seo p53 regulation of DNA excision repair pathways Mutagenesis, March 1, 2002; 17(2): 149 - 156. [Abstract] [Full Text] [PDF]

				O. Kovalsky, F.-D. T. Lung, P. P. Roller, and A. J. Fornace Jr. Oligomerization of Human Gadd45a Protein J. Biol. Chem., October 12, 2001; 276(42): 39330 - 39339. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hollander, M. C. Articles by Fornace, A. J. Search for Related Content PubMed PubMed Citation Articles by Hollander, M. C. Articles by Fornace, A. J., Jr.