Genotoxic Agents Increase Expression of Growth Arrest and DNA Damage–Inducible Genes gadd 153 and gadd 45 in Rat Pancreatic Islets

Abstract

Pancreatic beta-cells are able to repair themselves after some sublethal injuries in vitro. However, little is known of the nature of the repair mechanisms active in these cells. This study examined the expression of growth arrest and DNA damage--inducible genes gadd 153 and gadd 45 in pancreatic rat islets and in the clonal insulin secretory HIT-T15 cells. Rat pancreatic islets were exposed in vitro to the alkylating agents streptozocin or methyl methanesulfonate, or to the cytokine recombinant interleukin-1 beta. Islet exposure to STZ or MMS reduced insulin release by 40-50% over the next 4 h, whereas exposure to rIL-1 beta induced a 60% increase in insulin release over the same period. Both gadd 153 and gadd 45 mRNA were detectable in rat islets, and their levels were increased twofold after STZ exposure, whereas MMS induced a fivefold increase in gadd 153 and a twofold increase in gadd 45 mRNA. Islet exposure to rIL-1 beta did not affect the expression of gadd 153 or gadd 45. HIT cells exposed to STZ or MMS also exhibited an increased expression of both gadd 153 and gadd 45. Again, this increase in gadd mRNA was more marked after MMS exposure. Moreover, expression of both gadd 153 and gadd 45 after MMS exposure lasted for a longer period of time than after STZ treatment. The effects of MMS on the expression of both gadd genes were inhibited by actinomycin D, suggesting that transcription is necessary for acute gadd induction.(ABSTRACT TRUNCATED AT 250 WORDS)