Open AccessHypoxia‐induced irreversible S‐phase arrest involves down‐regulation of cyclin A
Author(s) -
Seim J.,
Graff P.,
Åmellem Ø.,
Landsverk K. S.,
Stokke T.,
Pettersen E. O.
Publication year - 2003
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1046/j.1365-2184.2003.00288.x
Subject(s) - hypoxia (environmental) , microbiology and biotechnology , chemistry , cyclin , biology , cell cycle , biochemistry , oxygen , apoptosis , organic chemistry
. We have studied hypoxia‐induced cell cycle arrest in human cells where the retinoblastoma tumour suppressor protein (pRB) is either functional (T‐47D cells) or abrogated by expression of the HPV18 E7 oncoprotein (NHIK 3025 cells). All cells in S phase are immediately arrested upon exposure to extreme hypoxia. During an 18‐h extreme hypoxia regime, the cyclin A protein level is down‐regulated in cells of both types when in S‐phase, and, as we have previously shown, pRB re‐binds in the nuclei of all T‐47D cells (Åmellem et al. 1996). Hence, pRB is not necessary for the down‐regulation of cyclin A during hypoxia. However, our findings indicate that re‐oxygenation cannot release pRB from its nuclear binding following this prolonged exposure. The result is permanent S‐phase arrest even after re‐oxygenation, and this is correlated with a complete and permanent down‐regulation of cyclin A in the pRB functional T‐47D cells. In contrast, both cell cycle arrest and cyclin A down‐regulation in S phase are reversed upon re‐oxygenation in non‐pRB‐functional NHIK 3025 cells after prolonged exposure to extreme hypoxia. Our results indicate that pRB is involved in permanent S‐phase arrest and down‐regulation of cyclin A after extreme hypoxia.