Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background. A detailed examination of the bone marrow in these mice identified reduced numbers of haematopoietic stem cells and a p53-dependent c-Kit down-regulation. These studies suggest that reduced Rpl27a increases p53 activity in vivo, further evident with a delay in tumorigenesis in mutant mice. Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation.
We report five cases of early rupture of cornual pregnancy with history of previous salpingectomy and cornual resection following in-vitro fertilization (IVF) and embryo transfer. We discuss the predisposing factors, diagnostic and therapeutic modalities in these patients. A high index of suspicion is required for an early diagnosis. It is imperative that the physicians who care for the patients be fully aware of the possibility of such a complication in a high risk population; therefore, appropriate counselling and close follow-up might help to avoid such obstetrical catastrophes, by termination of pregnancy, either surgically or medically.
Mouse oviducts synthesized maximal PGI2 during day 2-3 p.c., coinciding with the transformation of 2-cell embryos to morulae. The results suggest that oviduct-derived PGI2 may enhance embryo development in a paracrine fashion.
Animal studies unequivocally support the indispensable role of prostaglandin (PG) and cyclooxygenase (COX) in ovulation and implantation. Available data also suggest that PG and COX may be important in the transport of embryos. The effects of PGE(2) and PGF(2alpha) on the contractility of human tubal muscle have been studied extensively; the expression of COX in human fallopian tubes was also reported. Despite all these, two fundamentally important questions remained to be answered: 1) which PGs are produced by human fallopian tubes; and 2) which COX isoform(s) is expressed by the fallopian tubes. We used reverse-phase HPLC to study the metabolism of [1-(14)C] arachidonic acid by the fallopian tubes. We found that 6 keto-PGF(1alpha), a stable metabolite of prostacyclin (PGI), and PGE(2) constituted 56% +/- 10% and 35% +/- 10% (mean +/- SEM, four samples), respectively, of total eicosanoids synthesized. Western blot analysis revealed the expression of both COX isoforms. Immunohistochemistry study showed that both COX-1 and -2 were localized to nonciliated epithelia and tubal smooth muscle. In addition, COX-2 was also expressed in ciliated epithelial cells. Western blot analysis revealed the expression of PGI synthase (PGIS) and PGI receptor by fallopian tubes. Immunohistochemistry confirmed the expression of PGIS by luminal epithelia, tubal smooth muscle, vascular endothelial cells, and vascular smooth muscle cells. Iloprost, a PGI analog, inhibited the activities of circular and longitudinal muscles of the fallopian tube. Thus, the fallopian tube expresses both COX isoforms and PGIS. Furthermore, it is a source and a target of PGI. PGI and COX may be important to gamete function, embryo transport, and embryo development.
The lymphatic system plays important roles in draining fluids from interstitial spaces, absorbing lipids from the intestinal tract, and transporting white blood cells, including antigen-presenting cells, to lymphoid organs. Based on these functions, a number of disorders are associated with lymphatic vascular abnormalities including lymphedema, inflammatory disorders, and tumorassociated lymphangiogenesis. Therefore, understanding the mechanisms underlying the development of the lymphatic network can guide the treatment of lymphatic diseases. Activation of the transcription factor p53 has been implicated in several developmental syndromes where p53 is stimulated by cellular stressors like ribosomal imbalance. Once induced, p53 triggers important anti-proliferative programs like cell-cycle arrest and apoptosis and is therefore maintained at very low physiological levels during embryogenesis. Here, we report for the first time, a critical role of p53 overexpression in defects of lymphatic development. We generated two murine models that carry increased p53 activity induced by ribosomal stress concomitant with the loss of its negative regulators. These high-p53 models are embryonic lethal and present with cutaneous hemorrhaging, severe edema, and distended blood-filled lymphatic vessels. Cellular characterization of the lymphatic endothelial vessels at late-gestation show a reduced proliferation of endothelial cells, upregulation of the growth arrest marker p21 and a potential reduction of initial lymphatics that absorb the interstitial fluid. We also demonstrate that the lymphatic phenotypes are p53-dependent as genetic deletion of one copy of p53 or pharmacologic inhibition of p53 abolishes the cutaneous hemorrhaging, drastically reduces the edema, and rescues the embryonic lethality. Importantly, we detected overexpression of p53 in lymphatic endothelium of lymphedema associated disorders, linking our murine findings to the human disease. Taken together, we discovered that wild type p53 plays a central role in lymphedema predominantly through cell cycle arrest. Our findings indicate that targeting the p53 pathway, an unrecognized mechanism thus far in the genesis of lymphatic deficiencies, may offer therapeutic options for treating incurable lymphatic maladies.
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