Identification of DH IC-2 as a HIF-1 independent protein involved in the adaptive response to hypoxia in tumor cells: A putative role in metastasis.
The master regulator of the adaptive response to hypoxia is HIF-1. However, while some data show that HIF-1 can control more than 80% of the genes induced under hypoxia, other experiments clearly demonstrate that a part of the hypoxic response is independent of HIF-1. The goal of this study was to identify some of these HIF-1 independent factors and to investigate their functional role in the adaptation of tumor cells to hypoxia. We show that the cytoplasmic dynein intermediate chain 2 (DH IC-2), a component of an intracellular ATPase minus-end directed tubulin-based motile complex, was stabilized and post-translationally modified under hypoxia in a HIF-1 independent way. We identified this modification as a phosphorylation by protein kinase C, which is inhibited under hypoxia. In parallel, the migration of HepG2 cells was enhanced under hypoxia. Cell migration was also increased, to the same extent, by the invalidation of DH IC-2 using siRNA. Taken together, these results suggest that under hypoxia, a specific modification of DH IC-2 may modulate its activity, and in turn promote cell migration. These results are important to better understand cancer development since they highlight a HIF-1 independent mechanism, which may be involved in metastasis.
Pyr dit Ruys
Sebastien
S
URBC, University of Namur-FUNDP, B-5000 Namur, Belgium.
Delaive
Edouard
E
Demazy
Catherine
C
Dieu
Marc
M
Raes
Martine
M
Michiels
Carine
C
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D002465:Cell Movement; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering
D051793:Hypoxia-Inducible Factor 1; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011493:Protein Kinase C; D004398:Dyneins