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1.
Fragmentation is frequently observed in animal and human embryosobtained via in-vitro fertilization (IVF), and is known to beassociated with decreased pregnancy rates and poor survivalfollowing cryopreservation. We postulate that embryo fragmentationis a consequence of activated programmed cell death (PCD) andsubsequent apoptosis and discuss evidence of morphological,histological and biochemical features compatible with the occurrenceof PCD in preimplantation embryos. If PCD is an underlying causeof the high incidence of the fragmentation seen in human pre-embryos,it remains to be determined whether this is reflective of thenatural incidence of lethal chromo somes in the human populationor due to the IVF procedure and culture conditions. 相似文献
2.
Louise Bergeron Gloria I. Perez Glen Macdonald Lianfa Shi Yi Sun Andrea Jurisicova Sue Varmuza Keith E. Latham Jodi A. Flaws Jessica C.M. Salter Hideaki Hara Michael A. Moskowitz En Li Arnold Greenberg Jonathan L. Tilly Junying Yuan 《Genes & development》1998,12(9):1304-1314
During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development. 相似文献
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4.
Cinà DP Onay T Paltoo A Li C Maezawa Y De Arteaga J Jurisicova A Quaggin SE 《Journal of the American Society of Nephrology : JASN》2012,23(3):412-420
Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors. 相似文献
5.
Gonen Noa Casper Robert F. Jurisicova Andrea Yung Yuval Friedman-Gohas Moran Orvieto Raoul Haas Jigal 《Journal of assisted reproduction and genetics》2021,38(9):2301-2305
Journal of Assisted Reproduction and Genetics - To evaluates the effect of different modes of final follicular maturation triggering on the degree of apoptosis of granulosa cells (GCs) and the... 相似文献
6.
TAp73 knockout shows genomic instability with infertility and tumor suppressor functions 总被引:2,自引:0,他引:2
Tomasini R Tsuchihara K Wilhelm M Fujitani M Rufini A Cheung CC Khan F Itie-Youten A Wakeham A Tsao MS Iovanna JL Squire J Jurisica I Kaplan D Melino G Jurisicova A Mak TW 《Genes & development》2008,22(19):2677-2691
The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and DeltaNp73, with opposing pro- and anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles of p73 isoforms in cellular events such as tumor initiation, embryonic development, and cell death remain unclear. To determine which aspects of p73 function are attributable to the TAp73 isoforms, we generated and characterized mice in which exons encoding the TAp73 isoforms were specifically deleted to create a TAp73-deficient (TAp73(-/-)) mouse. Here we show that mice specifically lacking in TAp73 isoforms develop a phenotype intermediate between the phenotypes of Trp73(-/-) and Trp53(-/-) mice with respect to incidence of spontaneous and carcinogen-induced tumors, infertility, and aging, as well as hippocampal dysgenesis. In addition, cells from TAp73(-/-) mice exhibit genomic instability associated with enhanced aneuploidy, which may account for the increased incidence of spontaneous tumors observed in these mutants. Hence, TAp73 isoforms exert tumor-suppressive functions and indicate an emerging role for Trp73 in the maintenance of genomic stability. 相似文献
7.
Bcl-2 family members are important regulators of cell fate in normal organ development and in disease status. Pro- and anti-apoptotic members of this family function through a complex network of homo- and hetero-dimers to determine whether a cell lives or dies. Members of the Bcl-2 family are classically recognized for their role in apoptosis, yet emerging evidence has highlighted their importance in the regulation of cell cycle. Cellular proliferation, differentiation and death accompany early placental development of the trophoblast lineage. We have recently reported on the expression and function of two Bcl-2 family members in normal placental development, namely the pro-apoptotic Mtd/Bok, and its anti-apoptotic partner Mcl-1 and have found that their expression is upregulated by low oxygen, a key mediator of trophoblast cell proliferation in early placentation. Interestingly, we have also reported that the expression of the Mtd/Mcl-1 system is altered in preeclampsia, a placental pathology associated with a status of oxidative stress and typically characterized by an immature proliferative trophoblast phenotype and excessive trophoblast cell death. In this pathology levels of pro-apototic Mtd-L and Mtd-P are increased and anti-apoptotic Mcl-1 is cleaved in to a pro-apoptotic isoform. Disruption in Mtd/Mcl-1 expression seen in preeclampsia may contribute to both the increased apoptosis and hyperproliferative nature of this disorder. 相似文献
8.
Richard Tomasini Katsuya Tsuchihara Chiharu Tsuda Suzanne K. Lau Margareta Wilhelm Alessandro Ruffini Ming-sound Tsao Juan L. Iovanna Andrea Jurisicova Gerry Melino Tak W. Mak 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(3):797-802
The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73−/−) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73−/− mice show a high incidence of spontaneous tumors. Moreover, TAp73−/− mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells. 相似文献
9.
Effect of maternal age and conditions of fertilization on programmed cell death during murine preimplantation embryo development 总被引:3,自引:3,他引:3
Jurisicova A; Rogers I; Fasciani A; Casper RF; Varmuza S 《Molecular human reproduction》1998,4(2):139-145
One of the major morphological anomalies observed in many human pre-
embryos is extensive cellular fragmentation. Previously we confirmed that
embryo fragmentation seemed to be associated with the activation of
programmed cell death (PCD). The purpose of our experiments was to
establish a rate for murine embryo fragmentation in vivo after hormonal
stimulation in young versus older females and to compare it with the rate
of embryo fragmentation during in-vitro fertilization (IVF). While murine
maternal age beyond 40 weeks increased the rate of embryo fragmentation
following in-vivo fertilization (P = 0.001), oocytes from females of all
ages had a uniformly high rate of fragmentation when fertilized in vitro
(33%). None of the fragmented murine embryos proceeded further in
development. In the mouse, fragmentation occurs exclusively during the
first cell cycle. Furthermore, IVF significantly reduced the rate of
blastocyst formation (P = 0.0001) and decreased the mean cell number at the
blastocyst stage in comparison with embryos produced in vivo (P <
0.0001). The cell death index was significantly affected by both maternal
age (P = 0.005) and IVF (P = 0.0001). Identification of specific factors
which trigger PCD, especially those associated with IVF, may enable us to
lower the rates of fragmentation in preimplantation embryos and thereby
increase pregnancy rates after human IVF.
相似文献
10.
Yaakov Bentov Andrea Jurisicova Shlomit Kenigsberg Robert F. Casper 《Journal of assisted reproduction and genetics》2016,33(1):85-94