Cyclin-dependent Kinase Inhibitor 2A (Placental Senescence Marker) on Labor-related Signals

Overview

Onset of labor in human is initiated by progesterone withdrawal. Over many decades researchers had proposed hypotheses to explain the functional withdrawal of progesterone. These hypotheses were through the sequestration of active progesterone by corticosteroid-binding globulin, a decrease in active progesterone metabolite levels and changes in the ratio of progesterone receptor (PR) isoforms (nuclear progesterone receptors A (nPRA) and nuclear progesterone receptors B (nPRB)). Progesterone performs its action non-genomically through binding to membrane receptors and genomically via binding to nPRs. PRA is the less active or inactive form of progesterone receptors and shorter in amino acid sequence than PRB, the active form of the receptors.

Another mechanism was done through transcriptional co-activators, repressors inflammation resulting in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) mediated PR suppression. Previous study had explored that the uterine myometrium as the site of this functional withdrawal. There is also a clock that can determine the length of human pregnancy resides in the placenta and functional progesterone withdrawal likely occurs in this organ as well. Ageing is a process that causes deterioration in function at the cellular, tissue and organ levels. Telomeres are protective caps made of nucleoprotein molecules located at the end of chromosomes and are necessary for protection against breaks at DNA ends, fusion of chromosome ends and chromosome degradation. Telomeres are shortened with each cell division. The rate at which this occurs is accelerated by certain stressors such as oxidative stress. When telomeres reach a dangerously short length the process of cellular senescence initiates through which cells irreversibly stop growing and dividing by arresting their cell cycle and gradually ageing (becoming senescent). Cellular senescence is a state of irreversible cell cycle arrest resulting from high levels of P16 INK4a as well as tumour 15 suppressors p53 and retinoblastoma tumour suppressor protein. Senescent cells markedly have an ability to change gene expression patterns with overexpression of anti-apoptotic Bcl-2 leading to resistance to apoptosis and in parallel increase NFκB activity results in the expression of proinflammatory cytokines and chemokines. As pregnancy comes to term, decidual cells show many features of senescence including secretion of senescence-associated secretory phenotype (SASP) factors such as interleukin-6 (IL-6). A gradual process of decidual senescence may be critical for driving the cellular and tissue changes that contribute to labor onset at term. If ageing of the placenta normally determines pregnancy duration, this means that premature placental ageing will lead to preterm labor onset. According to World Health Organization (WHO), the American Academy of Pediatrics (AAP), and the American College of Obstetricians and Gynecologists (ACOG), preterm birth is defend as babies born alive before 37 weeks of pregnancy are completed. Each year, 15million babies are born preterm in the world. The National Center for Health Statistics of the Centers for Disease Control and Prevention generally reports data on three categories of preterm birth: overall preterm (\< 37 weeks 'gestation), moderately preterm (between 32 and 36 weeks' gestation) and very preterm births (\< 32 weeks' gestation). Late preterm infants are born at a gestational age between 34 weeks and less than37 weeks.