gadd153 is a mammalian gene whose expression is increased in response to a variety of stresses including DNA damage and growth arrest. It encodes a 19 kd protein with homology to the CCAAT/enhancer-binding protein (C/EBP) family of transcriptional activators. There is evidence to suggest that gadd153 functions as a negative regulator of these positive transcriptional regulators, but the relationship between this purported function and its expression in response to growth arrest is unclear. In this project, studies have focused on determining mechanisms responsible for regulating gadd153 expression in response to diverse growth inhibitory stimuli. The cessation of growth which occurs when cells are grown to high density in the absence of medium replacement (high density medium depletion; HDMD) has been shown to result in the induction of gadd153 mRNA. This induction is reversible and can be transferred to proliferating cells by the addition of medium from HDMD-arrested cells. Both transcriptional and posttranscriptional events are involved in controlling the response. Deletion analysis of the gadd153 promoter region indicated that major elements necessary for transcriptional activation of the gene reside in a region between -778 and -250 relative to the transcriptional start site. Several consensus sequences corresponding to interleukin 6 (IL-6) response elements (IL-6RE) as well as a possible C/EBP binding site are present within this region. Preliminary evidence suggests that the IL-6RE sites play a role in mediating the response. Glucose deprivation also leads to the induction of gadd153 mRNA and contributes, at least in part, to the HDMD-mediated gadd153 expression. However, additional mechanisms are involved. Nuclear run-on assays have shown that the effect of glucose deprivation is primarily at the transcriptional level, but surprisingly, glucose deprivation does not activate the same gadd153 promoter fragment (-778 to +21) that is responsive to HDMD, suggesting that sequences outside of the 800 bp fragment tested are necessary for glucose-regulated expression of gadd153.
| Maynard, Scott; Schurman, Shepherd H; Harboe, Charlotte et al. (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30:2-10 |
| Muftuoglu, Meltem; de Souza-Pinto, Nadja C; Dogan, Arin et al. (2009) Cockayne syndrome group B protein stimulates repair of formamidopyrimidines by NEIL1 DNA glycosylase. J Biol Chem 284:9270-9 |
