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Articles by J. W. Park
Total Records ( 2 ) for J. W. Park
  Y. M Lee , J. H Lim , Y. S Chun , H. E Moon , M. K Lee , L.E Huang and J. W. Park

The interplay among hypoxia-inducible factor 1-alpha (HIF-1), p53 and human orthologue of murine double minute 2 (Hdm2) has been introduced as a key event in tumor promotion and angiogenesis. Recently, nutlin-3, a small-molecule antagonist of Hdm2, was demonstrated to inhibit the HIF-1-mediated vascular endothelial growth factor production and tumor angiogenesis. Yet, the mechanism by which nutlin-3 inhibits HIF-1 is an open question. We here addressed the mode-of-action of nutlin-3 with respect to the HIF-1–p53–Hdm2 interplay. The effect of nutlin-3 on HIF-1 function was examined by reporter analyses, immunoprecipitation and immunoblotting. Nutlin-3 downregulated HIF-1, which occurred p53-dependently but von Hippel-Lindau-independently. On the contrary, nutlin-3 blunted the hypoxic induction of vascular endothelial growth factor by inactivating HIF-1 even in p53-null cells. The C-terminal transactivation domain (CAD) of HIF-1 was inactivated by nutlin-3, and furthermore, the factor-inhibiting hypoxia-inducible factor (FIH) hydroxylation of Asn803 was required for the nutlin-3 action. In terms of protein interactions, Hdm2 competed with FIH in CAD binding and inhibited the Asn803 hydroxylation both in vivo and in vitro, which facilitated p300 recruitment. Moreover, nutlin-3 reinforced the FIH binding and Ans803 hydroxylation by inhibiting Hdm2. In conclusion, Hdm2 functionally activates HIF-1 by inhibiting the FIH interaction with CAD, and the Hdm2 inhibition by nutlin-3 results in HIF-1 inactivation and vascular endothelial growth factor suppression. The interplays among HIF-1, Hdm2, FIH and p300 could be potential targets for treating tumors overexpressing HIF-1.

  S. J Park , Y. S Chun , K. S Park , S. J Kim , S. O Choi , H. L Kim and J. W. Park

Hypoxic inhibition of K+ current is a critical O2-sensing mechanism. Previously, it was demonstrated that the cooperative action of TASK-1 and NADPH oxidase-4 (NOX4) mediated the O2-sensitive K+ current response. Here we addressed the O2-sensing mechanism of NOX4 in terms of TASK-1 regulation. In TASK-1 and NOX4-coexpressing human embryonic kidney 293 cells, hypoxia (5% O2) decreased the amplitude of TASK-1 current (hypoxia-ITASK-1). To examine whether reactive oxygen species (ROS) mediate the hypoxia-ITASK-1, we treated the cells with carbon monoxide (CO) which is known to reduce ROS generation from the heme-containing NOX4. Unexpectedly, CO failed to mimic hypoxia in TASK-1 regulation, rather blocked the hypoxia-ITASK-1. Moreover, the hypoxia-ITASK-1 was neither recovered by H2O2 treatment nor prevented by antioxidant such as ascorbic acid. However, the hypoxia-ITASK-1 was noticeably attenuated by succinyl acetone, a heme synthase inhibitor. To further evaluate the role of heme, we constructed and expressed various NOX4 mutants, such as HBD(–) lacking the heme binding domain, NBD(–) lacking the NADPH binding domain, FBD(–) lacking the FAD binding domain, and HFBD(–) lacking both heme and FAD domains. The hypoxia-ITASK-1 was significantly reduced in HBD(–)-, FBD(–)-, or HFBD(–)-expressing cells, versus wild-type NOX4-expressing cells. However, NBD(–) did not affect the TASK-1 response to hypoxia. We also found that p22 is required for the NOX4-dependent TASK-1 regulation. These results suggest that O2 binding with NOX4 per se controls TASK-1 activity. In this process, the heme moiety and FBD seem to be responsible for the NOX4 regulation of TASK-1, and p22 might support the NOX4-TASK-1 interaction.

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