Role for casein kinase 2 in the regulation of HIF‐1 activity

International Journal of Cancer - Tập 117 Số 5 - Trang 764-774 - 2005
Denis Mottet1, Sébastien Pyr dit Ruys1, Catherine Demazy1, Martine Raes1, Carine Michiels1
1Laboratory of Biochemistry and Cellular Biology, University of Namur, Namur, Belgium

Tóm tắt

AbstractHypoxia‐inducible factor‐1 (HIF‐1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF‐1 activity occurs at multiple levels in vivo. The HIF‐1α subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF‐1α degradation, but also increase in the transactivation activity of HIF‐1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/threonine kinase, in the regulation of HIF‐1 activity. Hypoxia was capable of increasing the expression of the β subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the α subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6‐dichloro‐1‐β‐D‐ribofuranosyl‐benzimidazole), TBB (4,5,6,7‐tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2α, were shown to inhibit HIF‐1 activity as measured by a reporter assay and through hypoxia‐induced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF‐1α protein level. DNA‐binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF‐1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF‐1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. © 2005 Wiley‐Liss, Inc.

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Tài liệu tham khảo

10.1146/annurev.cellbio.15.1.551

10.1038/nm0603-677

10.1093/emboj/17.11.3005

10.1002/1097-0142(20000601)88:11<2606::AID-CNCR25>3.0.CO;2-W

Zhong H, 1999, Overexpression of hypoxia‐inducible factor 1alpha in common human cancers and their metastases, Cancer Res, 59, 5830

10.1128/MCB.21.10.3436-3444.2001

10.1073/pnas.92.12.5510

10.1096/fj.01-0944rev

10.1074/jbc.274.10.6519

10.1038/35017054

10.1073/pnas.190332597

10.1093/emboj/19.16.4298

10.1126/science.1059817

10.1126/science.1059796

10.1126/science.1068592

10.1128/MCB.22.9.2984-2992.2002

10.1016/S0014-5793(00)01181-9

10.1074/jbc.274.46.32631

10.1074/jbc.M209702200

10.1074/jbc.M201307200

10.1096/fj.02-0473rev

10.1073/pnas.94.12.6110

10.1016/S0962-8924(02)02279-1

10.1021/bi00488a034

10.1016/0092-8674(92)90311-Y

10.1074/jbc.272.21.13489

10.1128/MCB.16.4.1604

10.1023/A:1006850009017

10.1128/MCB.16.7.3554

10.1128/MCB.16.3.899

10.1074/jbc.M009134200

10.1074/jbc.275.10.6850

10.1074/jbc.M002446200

10.1074/jbc.M009275200

10.4049/jimmunol.167.9.4919

10.1074/jbc.M204221200

10.1002/(SICI)1096-9071(199608)49:4<264::AID-JMV2>3.0.CO;2-1

10.1042/bj3550347

Zien P, 2003, Selectivity of 4,5,6,7‐bromobenzimidazole (TBBZ) as an ATP‐competitive potent inhibitor of protein kinase CK2 from various sources, Cell Mol Biol Lett, 8, 613

10.1042/bj3640041

10.1042/bj20030674

10.1074/jbc.272.17.11205

10.1093/nar/29.4.e21

10.1074/jbc.M002697200

10.1006/bbrc.1995.2674

10.1128/MCB.16.4.1401

10.1096/fj.02-1062fje

10.4049/jimmunol.164.8.4292

10.1016/S0167-4781(02)00484-0

10.1074/jbc.270.22.13333

10.1161/01.RES.77.3.638

10.1038/ki.1997.79

10.1042/bj3270419

10.1006/excr.2001.5180

10.1016/S0301-0082(99)00026-X

10.1038/349132a0

10.1016/j.febslet.2004.08.036

10.1016/0014-5793(95)01497-7

10.1007/978-1-4615-5371-7_7

10.1023/A:1006854109926

10.1038/32925

10.1074/jbc.C200694200

10.1074/jbc.273.20.11995

10.1038/sj.onc.1206434

10.1093/emboj/20.7.1630

10.1093/emboj/cdg127

10.1080/15216540252774766

10.1128/MCB.22.1.12-22.2002

10.1128/MCB.22.8.2515-2523.2002

10.1074/jbc.271.23.13868

10.1006/jmbi.2000.3630

10.1002/jcp.10176

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International Journal of Cancer

Tập 117 Số 5

764-774

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