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

Christelle de Renty; Melvin L DePamphilis; Zakir Ullah

doi:10.1371/journal.pone.0097434

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

PLoS One. 2014 May 21;9(5):e97434. doi: 10.1371/journal.pone.0097434. eCollection 2014.

Authors

Christelle de Renty¹, Melvin L DePamphilis¹, Zakir Ullah²

Affiliations

¹ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
² Department of Biology, School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Apoptosis / genetics*
Cell Cycle / genetics
Cell Differentiation
Cell Line
Cell Nucleus / metabolism
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21 / genetics*
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / genetics*
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Cyclin-Dependent Kinase Inhibitor p57 / genetics*
Cyclin-Dependent Kinase Inhibitor p57 / metabolism
Cytosol / metabolism
DNA Damage
Gene Expression Regulation
Giant Cells / cytology
Giant Cells / metabolism*
HEK293 Cells
Humans
Mice
NIH 3T3 Cells
Phosphorylation
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Trophoblasts / cytology
Trophoblasts / metabolism*

Substances

Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p57
Cyclin-Dependent Kinase Inhibitor p27
Akt1 protein, mouse
Proto-Oncogene Proteins c-akt

Grants and funding

This work was supported by the NICHD intramural research program and by LUMS University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.