0000000000116735
AUTHOR
Thomas Grombacher
p53 is involved in regulation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) by DNA damaging agents
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is inducible by genotoxic stress. MGMT induction results from transcriptional activation of the MGMT gene which is a specific response to DNA damage. A possible factor involved in triggering MGMT induction might be p53, because both p53 and MGMT are activated by DNA breaks. To study the effect of p53 on induction of the MGMT gene, we compared the presence of functional wild-type (wt) and mutant p53 with MGMT expression level in various mouse fibroblasts and rat hepatoma cell lines upon genotoxic treatment. Cells which responded to ionizing radiation (IR) by MGMT induction displayed functional p53, whereas in cells not expr…
Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes.
Repair of alkylated bases in DNA is performed by O6-methylguanine-DNA methyltransferase (MGMT) and a set of enzymes of the base excision repair pathway involving N-methylpurine-DNA glycosylase (MPG), apurinic endonuclease (APE), DNA polymerase beta (Pol beta) and DNA ligase. The level of expression of these enzymes may exert a profound effect on resistance of cells towards alkylating drugs. We have comparatively analyzed the expression of MGMT and the different base excision repair genes in rat hepatoma cells (line H4IIE) after exposure to alkylating agents, X-rays and the glucocorticoid hormone dexamethasone. Furthermore, the effect of these agents on the activity of the cloned human MGMT …
Transgenic systems in studies on genotoxicity of alkylating agents: critical lesions, thresholds and defense mechanisms
Abstract Transgenic systems, both cell lines and mice with gain or loss of function, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense against genotoxic mutagens and carcinogens. In this review, questions have been addressed concerning the use of transgenic systems in elucidating critical primary DNA lesions, their conversion into genotoxic endpoints, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair protein alkyltransferase (MGMT) is decisive for protection against methylating and chloroethylating compounds. Protection pertains also…
Constitutive expression and inducibility of O6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in rat liver cells exhibiting different status of differentiation
AbstractWe have analyzed the expression of the DNA repair genes O6-methylguanine-DNA methyltransferase (MGMT) and N-methylpurine-DNA glycosylase (MPG) at RNA and protein activity level in primary rat hepatocytes in vitro and various rat hepatoma cell lines exhibiting different status of differentiation. The basal level of MGMT mRNA and activity correlated well with the degree of differentiation, as measured by tyrosine aminotransferase (TAT) mRNA expression. Induction of MGMT mRNA and protein activity by X-ray and Nmethyl-N′-nitro-N-nitrosoguanidine (MNNG) treatment was most pronounced in the well-differentiated hepatocytes and in various differentiated hepatoma cell lines (up to 6-fold). T…
Inducible Responses and Protective Functions of Mammalian Cells Upon Exposure to UV Light and Ionizing Radiation
In mammalian cells, ultraviolet (UV) light as well as ionizing radiation (IR) transcriptionally activate the early-responsive genes c-fos, c jun,junB and junD. The induction of fos and jun by UV-C is currently understood to occur via activation of the EGF receptor and the Ras, Raf, ERK and JNK cascade leading ultimately to phosphorylation of transcription factors such as Fos and Jun (AP-1). This, finally, gives rise to transcriptional activation of AP-1 dependent target genes. Another gene we have recently demonstrated to be immediate-early inducible upon UV-irradiation encodes the Ras-related small GTPase RhoB. The pathway of rhoB induction appears to be different from fos/jun because (i) …