Abstract
ABSTRACTPDCD2 (programmed cell death domain 2) is a highly conserved, zinc finger MYND domain-containing protein essential for normal development in the fly, zebrafish and mouse. The molecular functions and cellular activities of PDCD2 remain unclear. In order to better understand the functions of PDCD2 in mammalian development, we have examined PDCD2 activity in mouse blastocyst embryos, as well as in mouse embryonic stem cells (ESCs) and embryonic fibroblasts (MEFs). We have studied mice bearing a targeted PDCD2 locus functioning as a null allele through a splicing gene trap, or as a conditional knockout, by deletion of exon2 containing the MYND domain. Tamoxifen-induced knockout of PDCD2 in MEFs, as well as in ESCs, leads to defects in progression from the G1 to the S phase of cell cycle, associated with increased levels of p53 protein and p53 target genes. G1 prolongation in ESCs was not associated with induction of differentiation. Loss of entry into S phase of the cell cycle and marked induction of nuclear p53 were also observed in PDCD2 knockout blastocysts. These results demonstrate a unique role for PDCD2 in regulating the cell cycle and p53 activation during early embryonic development of the mouse.
Highlights
IntroductionPDCD2 (programmed cell death protein 2) is a highly conserved, zinc finger MYND domain-containing protein of unknown molecular function
PDCD2 is a highly conserved, zinc finger MYND domain-containing protein of unknown molecular function
Our results demonstrate an important function of PDCD2 in proliferation, for the G1/S phase transition of the cell cycle in mouse embryonic fibroblasts (MEFs) and embryonic stem cells (ESCs), as well as in mouse blastocyst embryos
Summary
PDCD2 (programmed cell death protein 2) is a highly conserved, zinc finger MYND domain-containing protein of unknown molecular function. PDCD2 RNA was originally identified in thymocytes undergoing programmed cell death (Owens et al, 1991; Vaux and Hacker, 1995), and has been suggested to play a role in apoptotic regulation, in lymphoma cells (Baron et al, 2007; Baron et al, 2010). Previous studies have suggested an important role for PDCD2 in development and stem cell activity. Mutations in the Drosophila melanogaster PDCD2 homolog, zfrp, result in defective hematopoietic stem cell (HSC) differentiation and altered development of ovarian stem cells (Minakhina et al, 2007; Minakhina and Steward, 2010; Minakhina et al, 2014). PDCD2 knockout in the mouse results in embryonic lethality around 3.5 dpc suggesting a critical role in embryonic development at the times of zygotic gene activation and implantation (Mu et al, 2010)
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