PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53.
Type I IFN-induced expression of dsRNA-activated protein kinase (PKR) during viral infection is a well-established antiviral mechanism. However, little is known about the expression of PKR in the context of p53 and about PKR involvement in p53-mediated tumor suppression. Here, we report that PKR is a p53 target gene and plays an important role in the tumor-suppressor function of p53. Activation of p53 by genotoxic stress induces a significant level of PKR expression by acting on the newly identified cis-acting element (ISRE), which is separated from the IFN-stimulated responsive element on the PKR promoter, resulting in translational inhibition and cell apoptosis. The genotoxin-mediated inhibition of translation is associated with the p53/PKR/elF2a (eukaryotic initiation factor-2alpha) pathway. To some extent, p53 activation induced by DNA damage facilitates cell apoptosis by activating PKR. PKR-knockdown human colon cancer cells grew rapidly in nude mice and proved resistant to anti-cancer drugs. These data indicate that p53-mediated tumor suppression can be attributed at least in part to the biological functions of PKR induced by p53 in genotoxic conditions.
Department of Biological Sciences, Sungkyunkwan University, Choenchoen-Dong, Jangan-Gu, Suwon, Gyeonggi-Do 440-746, South Korea.
Cheol-Hee
CH
Yoon
Eun-Soo
ES
Lee
Dae-Seog
DS
Lim
Yong-Soo
YS
Bae
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009153:Mutagens / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D019892:eIF-2 Kinase / Q000502:physiology*
D000970:Antineoplastic Agents; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase