Suppression of p53-dependent senescence by the JNK signal transduction pathway

The JNK signaling pathway is implicated in the regulation of the AP1 transcription factor and cell proliferation. Here, we examine the role of JNK by using conditional and chemical genetic alleles of the ubiquitously expressed murine genes that encode the isoforms JNK1 and JNK2. Our analysis demonstrates that JNK is not essential for proliferation. However, JNK is required for expression of the cJun and JunD components of the AP1 transcription factor, and JNK-deficient cells exhibit early p53-dependent senescence. These data demonstrate that JNK can act as a negative regulator of the p53 tumor suppressor

Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation

Embryo implantation in the uterus is a critical step in mammalian reproduction, requiring preparation of the uterus receptive to blastocyst implantation. Uterine receptivity, also known as the window of implantation, lasts for a limited period, and it is during this period blastocysts normally implant. Ovarian steroid hormones estrogen and progesterone (P(4)) are the primary regulators of this process. The immunophilin FKBP52 serves as a cochaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues. Here we show a critical role for FKBP52 in mouse implantation. This immunophilin has unique spatiotemporal expression in the uterus during implantation, and females missing the Fkbp52 gene have complete implantation failure due to lack of attainment of uterine receptivity. The overlapping uterine expression of FKBP52 with nuclear progesterone receptor (PR) in wild-type mice together with reduced P(4) binding to PR, attenuated PR transcriptional activity and down-regulation of several P(4)-regulated genes in uteri of Fkbp52(-/-) mice, establishes this cochaperone as a critical regulator of uterine P(4) function. Interestingly, ovulation, another P(4)-mediated event, remains normal. Collectively, the present investigation provides evidence for an in vivo role for this cochaperone in regulating tissue-specific hormone action and its critical role in uterine receptivity for implantation