PGA2-induced HO-1 attenuates G2M arrest by modulating GADD45α expression

초록

Prostaglandin (PG) A(2), a cyclopentenone PG, arrested the growth of U2OS cells in the G(2)M phase. While inducing G(2)M arrest, PGA(2) increased the expression of heme oxygenase-1 (HO-1) at the level of transcription along with the accumulation of ROS and the activation of MAPKs including JNK, p38MAPK, and ERK1/2. Among the MAPKs, the inhibition of p38MAPK by a specific chemical inhibitor SB203580, or by RNA interference, but not JNK or ERK1/2, attenuated the PGA(2)-induced transcription of HO-1. N-acetylcysteine (NAC), a ROS scavenger, prevented PGA(2)-induced G(2)M arrest, p38MAPK activation and transcriptional induction of HO-1. PGA(2) also stimulated GADD45 alpha expression at the level of transcription, and the knockdown of GADD45 alpha repressed PGA(2)-induced G(2)M arrest. Finally, the knockdown of the HO-1 protein elevated PGA(2)-induced GADD45 alpha expression as well as G(2)M arrest. Collectively, these results suggest that PGA(2) causes an increase in ROS accumulation which initiates both HO-1 transcription via p38MAPK, and G(2)M arrest via GADD45 alpha transcription, and HO-1 attenuates G(2)M arrest by modulating the expression of GADD45 alpha.

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