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A Mammalian Cell Cycle Checkpoint Pathway Utilizing ~53 and GADD45 Is Defective in Ataxia-Telangiectasia

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A Mammalian Cell Cycle Checkpoint Pathway Utilizing ~53 and GADD45 Is Defective in Ataxia-Telangiectasia Cell, Vol. 71, 587-597, November 13, 1992, Copyright 0 1992 by Cell Press A Mammalian Cell Cycle Checkpoint Pathway Utilizing ~53 and GADD45 Is Defective in Ataxia-Telangiectasia Michael IB. Kastan,* Qimin Zhan,t Wafik S. El-Deiry,” ation (Hartwell and Weinert, 1989; Weinert and Hartwell, France Carrier,t Tyler Jacks,t William V. Walsh, l 1988, 1990). Beverly 5. Plunkett, l Bert Vogelstein, l Though cell cycle delays due to DNA damage have been and Albert J. Fornace, Jr.t observed for years in mammalian cells, little is known *The Johns Hopkins Oncology Center about the molecular mechanisms that control them. Re- 600 North Wolfe Street cently, we found that levels of the tumor suppressor Baltimore, Maryland 21287 nuclear protein ~53 transiently increase in temporal asso- tllaboratory of Molecular Pharmacology ciation with the transient decrease in replicative DNA syn- Nlational Cancer Institute thesis that follows exposure of human GelUsto y-irradiation B’ethesda, Maryland 20892 (Kastan et al., 1991). Since cells with wild-type ~53 genes *Center for Cancer Research exhibited transient arrests in both 61 and G2 after y-irradi- Massachussetts Institute of Technology ation, while cells with absent or mutant ~53 genes retained C:ambridge, Massachusetts 02139 only the G2 arrest, it appeared that wild-type ~53 played a critical role in the Gl arrest. This concept was further supported by the subsequent observations that transfec- Summary tion of wild-type p53 genes into malignant cells lacking endogenous ~53 genes partially restored the Gl arrest C:ell cycle checkpoints can enhance cell survival and after y-irradiation and that overexpression of a transfected liimit mutagenic events following DNA damage. Pri- mutant ~53 gene in tumor cells with wild-type endogenous mary murine fibroblasts became deficient in a Gl p53 genes abrogated the Gl arrest following y-irradiation clheckpoint activated by ionizing radiation (IF?) when (Kuerbitz et al., 1992). Since the tumor call lines used for b’oth wilcl-type ~53 alleles were disrupted. In addition, the transfection experiments had multiplt? genetic abnor- c~ells from patients with the radiosensitive, cancer- malities, however, it had still not been formally demon- prone disease ataxia-telangiectasia (AT) lacked the IR- strated that loss of p53 function alone, with no other ge- induced increase in ~53 protein levels seen in normal netic changes, was sufficient for loss of the Gl arrest. This aells. Finally, IR induction of the human GADD45 gene, is addressed here by evaluating the cell cycle progression an induction that is also defective in AT cells, was de- following y-irradiation of normal embryonic fibroblasts ob- plendent on wild-type p53 function. Wild-type but not tained from mice in which both ~53 genes have been dis- mlutant p53 bound strongly to a conserved element in rupted. the GADD45 gene, and a p53-containing nuclear fac- Ataxia-telangiectasia (AT) is a human aiutosomal reces- tor, which bound this element, was detected in ex- sive disorder with many phenotypic characteristics, includ- tracts from irradiated cells. Thus, we identified three ing hypersensitivity to ionizing radiation (IR), radioresis- participants (AT gene(s), ~53, and GADD45) in a signal tant DNA synthesis, a markedly increased incidence of transduction pathway that controls cell cycle arrest cancer, and progressive cerebellar ataxia with degenera- following DNA damage; abnormalities in this pathway tion of Purkinje cells (for reviews see McKinnon, 1987; probably contribute to tumor development. Gatti et al., 1991). It has been suggested ithat the inability of AT cells to cease replicating DNA following y-irradiation Introduction contributes to their hypersensitivity (Painter and Young, 1980). Interestingly, the lack of cessation of replicative Both prokaryotic and eukaryotic cells delay cell division DNA synthesis in AT cells following y-ray exposure (Ru- following damage of the DNA. Delays in progression from dolph and Latt, 1989) is virtually identical to the situation both Gl into S and from G2 into M occur in most organisms observed in cells with abnormal ~53 genes (Kastan et al., (Tolmach et al., 1977; Painter and Young, 1980; Lau and 1991; Kuerbitz et al., 1992). Therefore, a link between Pardee, 1982; Weinert and Hartwell, 1988; Kaufmann et the defect in AT and the signal transduction pathway that al., 1991; O’Connor et al., 1992). These cell cycle check- utilizes ~53 in causing the Gl arrest following y-irradiation points presumably exist to prevent both replication of a was investigated. If the AT phenotype were due to a defect damaged DNA template (the Gl arrest) and segregation proximal to ~53 in this pathway, AT cells would lack the of damaged chromosomes (the G2 arrest). It is thought induction of ~53 protein that is seen in normal cells follow- that thetransient delays at these checkpoints permit repair ing y-irradiation. Thus, ~53 protein Bevels were examined of the damaged DNA prior to these critical cellular func- in normal and AT cells following y-irradiation. tions and should thus enhance cell survival and limit propa- Recently, ~53 has been shown to be a sequence- gation of heritable genetic errors (Weinert and Hartwell, specific DNA-binding protein (Bargonetti etl al., 1991; Kern 1988). For example, mutations of the RADQ gene in yeast et al., 1991), and a genomic consensus sequence has result in a defect in the G2 checkpoint; these RAD9 mu- been elucidated that consists of two copies of a symmetric taints are radiosensitive compared with wild-type strains 10 bp motif separated by O-13 bp (El-Deiry et al., 1992). and exhibit increased genetic instability following y-irradi- When this consensus sequence was placed adjacent to a Cell 588 basal promoter linked to chloramphenicol acetyltransfer- copies of the e~do~e~ous p53 alleles had been ~~~r~~~~~ ase (CAT) or luciferase reporter genes, cotransfection of by homologous r such a construct with a ~53 expression vector into mam- unpublished data. malian cells resulted in induction of the reporter gene ated following exposure to y-rays. Cell (Kern et al., 1992; Funket al., 1992). In addition, wild-type was evaluated at very e ~53 can directly activate transcription in vitro (Farmer et al., 1992). Thus, a likely role for ~53 in a signaling mecha- nism that activates a Gi checkpoint after DNA damage is as a transcription factor that activates genes involved in negative growth control. Potential candidates for p53- inducible genes might be those that are differentially regu- lated after DNA damage and growth arrest. decrease in the ~erc~~taga of S phase cells fo The five growth arrest and DNA damage-inducible (or gadd) genes were initially isolated on the basisof induction after DNA damage in Chinese hamster ovary cells but have been subsequently found to be induced by DNA- damaging agents or other treatments eliciting growth ar- rest, such as serum reduction, in a wide variety of mamma- lian cells (Fornace et al., 1989b). In particular, the gadd45 and gadd153 genes have been found to be rapidly and coordinately induced by agents, such as methylmethane sulfonate (MMS), that produce high levels of base damage in DNA in every cell line examined, including human, ham- ster, murine, and rat cells (Fornace et al., 1989b, 1992). cussed previous~y~ a rapid increase in p53 protein Eeveis Recently, the human GADD45 gene was found to be rap- appears to be closely fin to the IR-induce idly induced by IR in lymphoblasts and fibroblasts (Papa- To investigate whether re is a defect in thanasiou et al., 1991). This IR response appeared to be dependent response pathway in AT, the ability o distinct from the gadd response to MMS and other base- of cell lines from AT patients to increase p53 p damaging agents because only GADD45 was strongly in- following exposure to IR was evaluated. duced and induction occurred with doses of IF? that pro- increases in p53 protein I duce relatively little DNA base damage. Interestingly, this mortalimed lymphoblasts f IR response was significantly reduced in four AT com- netically normai individuals were easily detected pared with four normal lymphoblast lines (Papathanasiou i~munoprecipitati0~ QF [%]methionine-I etal., 1991). Thefunctionof themammalianGADD45gene ure 2A) and ~rnrn~~~b~ots detecting p53 from ~h~~~-ce~~ is unknown, but it is highly conserved invertebratespecies . In ~~~~rast, no increase in (unpublished data; Papathanasiou et al., 1991). Based on was evident in lym~ho~las this information and on the recent finding that the IR induc- m~~oprecipitstio~ (Figure tion of GADD45 is absent in some human tumor cell lines (Fort-race et al., 1991), a role for p53 in the IR response of GADD45 was investigated. After demonstrating that IR induction of GADD45 is dependent on a wild-type p53 phe- notype, a conserved p53-binding site was identified in the human and hamster GAD045 genes and binding of p53 protein to this sequence was evaluated. Based on the re- codon 72 that occurs in some individuals KB~~hmafl et al., sults of these investigations, a model for the steps in this DNA damage-inducible signal transduction pathway re- sulting in a Gl arrest is presented. Abnormalities at any step in this pathway have the potential to affect cell survival and genomic integrity adversely following certain types of difference between p53 induction in normal cells and DNA damage, including IR, and thus also to contribute ta heterozygotes, however, will require exarn~~ati~~ of e cellular transformation. larger number of normal and AT heterozygote ceil lines. The induction of p53 protein was also evaluated in di Results loid fibroblasts from a normal individual and patient. As was seen in the lymphoblasts, while Cell Cycle Perturbations Following IR in Cells a normal ~~div~d~a~ increase p53 protein levels from ~53 Knockout Mice IR, no increase was evident in fibroblasts from an To demonstrate that loss of ~53 function alone, with no tient (Figure 2C).
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