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  • Cytoplasmic localization of p21 protects trophoblast giant cells from DNA damage induced apoptosis.

Cytoplasmic localization of p21 protects trophoblast giant cells from DNA damage induced apoptosis.

PloS one (2014-05-23)
Christelle de Renty, Melvin L DePamphilis, Zakir Ullah
ABSTRACT

Proliferating trophoblast stem cells (TSCs) can differentiate into nonproliferating but viable trophoblast giant cells (TGCs) that are resistant to DNA damage induced apoptosis. Differentiation is associated with selective up-regulation of the Cip/Kip cyclin-dependent kinase inhibitors p57 and p21; expression of p27 remains constant. Previous studies showed that p57 localizes to the nucleus in TGCs where it is essential for endoreplication. Here we show that p27 also remains localized to the nucleus during TSC differentiation where it complements the role of p57. Unexpectedly, p21 localized to the cytoplasm where it was maintained throughout both the G- and S-phases of endocycles, and where it prevented DNA damage induced apoptosis. This unusual status for a Cip/Kip protein was dependent on site-specific phosphorylation of p21 by the Akt1 kinase that is also up-regulated in TGCs. Although cytoplasmic p21 is widespread among cancer cells, among normal cells it has been observed only in monocytes. The fact that it also occurs in TGCs reveals that p57 and p21 serve nonredundant functions, and suggests that the role of p21 in suppressing apoptosis is restricted to terminally differentiated cells.

MATERIALS
Product Number
Brand
Product Description

Etoposide for system suitability, European Pharmacopoeia (EP) Reference Standard
Roche
5-Bromo-2′-deoxy-uridine Labeling and Detection Kit I, sufficient for ≤100 tests, kit of 1 (5 components), suitable for immunofluorescence
Sigma-Aldrich
Akt1 active human, recombinant, expressed in baculovirus infected Sf9 cells, ≥75% (SDS-PAGE)
Etoposide, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Etoposide, synthetic, 95.0-105.0%, powder