Hypoxia-induced irreversible S-phase arrest involves down-regulation of cyclin A.

Abstract:

: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 (Amellem 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.

journal_name

Cell Prolif

journal_title

Cell proliferation

authors

Seim J,Graff P,Amellem O,Landsverk KS,Stokke T,Pettersen EO

doi

10.1046/j.1365-2184.2003.00288.x

subject

Has Abstract

pub_date

2003-12-01 00:00:00

pages

321-32

issue

6

eissn

0960-7722

issn

1365-2184

journal_volume

36

pub_type

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