VDUP1 mediates nuclear export of HIF1alpha via CRM1-dependent pathway.
Hypoxia-inducible factor 1alpha (HIF1alpha) is a critical transcriptional factor for inducing tumor metastasis, and stabilized under hypoxia but degraded by von Hippel-Lindau protein (pVHL) under normoxia. For the maximal degradation of HIF1alpha, it must be exported to the cytoplasm via an unidentified transporter. Here, we demonstrate that vitamin D3 up-regulated protein 1 (VDUP1) associates with the beta-domain of pVHL and enhances the interaction between pVHL and HIF1alpha to promote the nuclear export and degradation of HIF1alpha hypoxia-independently. Blocking of VDUP1 translocation either by leptomycin B or by nuclear export signal mutation inhibited the nuclear export of pVHL/HIF1alpha and relieved the destabilization of HIF1alpha. VDUP1 suppressed cell invasiveness and tumor metastasis, which were also recovered by blocking of nuclear export. Taken together, these findings indicate that VDUP1 is a novel tumor suppressor which mediates the nuclear export of pVHL/HIF1alpha complex to destabilize HIF1alpha.
Shin
Daesung
D
Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon, Republic of Korea.
Jeon
Jun-Ho
JH
Jeong
Mira
M
Suh
Hyun-Woo
HW
Kim
Seyl
S
Kim
Hyoung-Chin
HC
Moon
Og-Sung
OS
Kim
Yong-Sung
YS
Chung
Jin Woong
JW
Yoon
Suk Ran
SR
Kim
Woo-Ho
WH
Choi
Inpyo
I
D021581:Active Transport, Cell Nucleus; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D028884:Karyopherins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000097606:Exportin 1 Protein
D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000097606:Exportin 1 Protein; C486715:TXNIP protein, human