Regulators of G-protein signaling family members, such as RGS2, are thought to primarily be involved in regulating the activity of second messenger systems by attenuating heterotrimeric G-protein actions. However, we found previously that RGS2 is predominantly located in the nucleus, not at the plasma membrane where most G-proteins exist, and that stressful conditions increased RGS2 expression. Here we report that induction of DNA damage-induced cell cycle arrest with camptothecin caused prolonged increases in RGS2, and decreases in RGS4, mRNA levels. Cell cycle arrest caused by nocodazole also increased RGS2, and decreased RGS4, mRNA levels. Additionally, using synchronization to minimize cell stress, RGS2 mRNA levels were low in G0 and G1, and elevated in the other phases of the cell cycle. These results demonstrate that RGS2 expression is coupled to cellular stress and the cell cycle, and that these conditions cause opposite effects on RGS2 and RGS4 mRNA levels.