Regulation of cell death and cell survival gene expression during ovarian follicular development and atresia

AbstractThe actin cytoskeleton is a well-known player in most vital cellular processes, but comparably little is understood about how the actin assembly machinery impacts programmed cell death pathways. In the current study, we explored roles for the human Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation factors in DNA damage-induced apoptosis. Inactivation of each WASP-family gene revealed that two, JMY and WHAMM, are required for rapid apoptotic responses. JMY and WHAMM enable p53-dependent cell death by enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation. The loss of JMY additionally results in significant changes in gene expression, including upregulation of the small G-protein RhoD. Depletion or deletion of RHOD increases cell death, suggesting that RhoD normally plays a key role in cell survival. These results give rise to a model in which JMY and WHAMM promote intrinsic cell death responses that can be opposed by RhoD.Author SummaryThe actin cytoskeleton is a collection of protein polymers that assemble and disassemble within cells at specific times and locations. Cytoskeletal regulators called nucleation-promoting factors ensure that actin polymerizes when and where it is needed, and many of these factors are members of the Wiskott-Aldrich Syndrome Protein (WASP) family. Humans express 8 WASP-family proteins, but whether the different factors function in programmed cell death pathways is not well understood. In this study, we explored roles for each WASP-family member in apoptosis and found that a subfamily consisting of JMY and WHAMM are critical for a rapid pathway of cell death. Furthermore, the loss of JMY results in changes in gene expression, including a dramatic upregulation of the small G-protein RhoD, which appears to be crucial for cell survival. Collectively, our results point to the importance of JMY and WHAMM in driving intrinsic cell death responses plus a distinct function for RhoD in maintaining cell viability.

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Anti-Apoptosis and Cell Survival Gene Expression Profile in LAD2 Cells

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2015.12.256 ◽

2016 ◽

Vol 137 (2) ◽

pp. AB76

Author(s):

Arnold S. Kirshenbaum ◽

Maarten Leerkes ◽

Avanti Desai ◽

Dean D. Metcalfe

Keyword(s):

Gene Expression ◽

Cell Survival ◽

Gene Expression Profile ◽

Expression Profile ◽

Survival Gene

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Aspects of Ovarian Function in a Line of Sheep with a Novel X-Linked Maternally-Imprinted Gene that is Associated with an Increased Ovulation Rate

10.26686/wgtn.16945789 ◽

2021 ◽

Author(s):

◽

Elisabeth Sheinach Feary

Keyword(s):

Gene Expression ◽

Pituitary Gland ◽

Ovarian Function ◽

Follicular Development ◽

Cell Types ◽

Ovulation Rate ◽

Chromosome 2 ◽

Ovarian Follicular Development ◽

Er Alpha ◽

Large Ovary

<p>Fecundity is a term that refers to the number of offspring produced per female. It combines fertility (i.e. ability to produce offspring) and prolificacy (i.e. number of offspring). Ovulation rate i.e. the number of mature eggs released from the ovaries during one reproductive cycle in sheep, as with other mammals, is controlled by an exchange of hormonal signals between the pituitary gland and the ovary. Genetic mutations affecting ovulation are commonly referred to as the fecundity genes (Fec). The most obvious outcome is the number of offspring produced. There is already evidence of a number of major genes affecting the ovulation rate in sheep, specifically the Booroola, Inverdale, Hanna and more recently the Woodlands gene. The sheep carrying the Woodlands gene arose because the mutation was first recognised on a farm in Woodlands, Southland, New Zealand. Woodlands have a novel, X-linked maternally-imprinted, fecundity trait referred to as FecX2w, where Fec = fecundity, X = X chromosome, 2= 2nd mutation identified on X and W= Woodlands. The studies in this thesis investigated ovarian follicular development in both 4-week old Woodland carrier (W+) and non-carrier (++) lambs and adult ewes and evaluated some aspects of the endocrine interactions between the ovary and pituitary gland. The purpose was to identify potential physiological effects of the FecX2w gene on ovarian function. A confounding issue during these studies was the discovery that a large ovary phenotype (LOP) which was present in many of the W+ but not ++ lambs at 4 weeks of age was in fact a coincidence and not linked to the FecX2w mutation. The key findings from the studies of lambs and/or ewes that were carriers (W+) or non-carriers (++) of the FecX2w gene were: 1. No genotype differences were present either in the numbers of primordial (i.e. Type 1/1a follicles) or developing preantral (i.e. Types 2-4 follicles); 2. Significant genotype differences were present in the numbers of small antral (Type 5) follicles (W+>++; p<0.05); 3. An earlier onset of antral follicular development in W+ vs. ++ ewes with irregularities in morphology between the basement membrane and stroma in the former; 4. No genotype differences in the onset of gene expression during follicular development or in the cell-types expressing GDF9, BMP15, alpha inhibin, beta A inhibin and beta B inhibin, FSHR, ER alpha, or ER beta; 5. No genotype differences in the levels of GDF9 or BMP15 gene expression in oocytes throughout follicular growth; 6. No genotype difference in the diameters that follicles reached in W+ vs. ++ ewes; 7. Some lambs at 4-weeks of age had unusually large ovaries with an exceptional level of antral follicular development that is reminiscent of a polycystic ovarian condition. The underlying cause of this condition is unknown. In conclusion, the physiological characteristics of ovarian follicular development in ewes with the FecX2w gene is different from that in ewes with the Booroola, Inverdale, Hanna or other recently identified mutations.</p>

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Gap junctions in IL-1β-mediated cell survival response to strain

Journal of Applied Physiology ◽

10.1152/japplphysiol.00477.2010 ◽

2011 ◽

Vol 110 (5) ◽

pp. 1425-1431 ◽

Cited By ~ 19

Author(s):

Jie Qi ◽

Liqun Chi ◽

Donald Bynum ◽

Albert J. Banes

Keyword(s):

Gene Expression ◽

Cell Death ◽

Cell Survival ◽

Connexin 43 ◽

Type I Collagen ◽

Cyclic Strain ◽

Marker Genes ◽

Type I ◽

Mechanical Stimuli

Mechanical stimuli play important roles in proliferation and differentiation of connective tissue cells, and development and homeostatic maintenance of tissues. However, excessive mechanical loading to a tissue can injure cells and disrupt the matrix, as occurs in tendinopathy. Tendinopathy is a common clinical problem in athletes and in many occupational settings due to overuse of the tendon. Moreover, interleukin (IL)-1β is generally considered to be a “bad” cytokine, activating NF-κb and cell death and inducing matrix metalloproteinase (MMPs 1, 2, 3) expression and matrix destruction. However, activated NF-κB can also drive a cell survival pathway. We have reported that cyclic strain induced tenocyte death in three-dimensional (3D) cultures, and IL-1β could promote cell survival under strain. Therefore, it was hypothesized that 1) cyclic strain could induce cell death in tenocytes as observed in pathologic tendons in vivo; 2) a gene expression profile indicative of tendinopathy could be identified; and 3) low-dose IL-1β could protect cells from strain-induced, tendinopathy-like changes. Human tenocytes were cultured in 3D type I collagen hydrogels and subjected to 3.5% elongation at 1 Hz for 1 h/day for up to 5 days with or without IL-1β. Real-time RT-PCR data showed that cyclic strain regulated the expression of tendinopathy marker genes in a manner similar to that found in pathological tendons from patients and that addition of IL-1β reversed the gene expression changes to control levels. Results of further studies showed that IL-1β may modulate cell survival through upregulating the expression of connexin 43, which is involved in the modulation of cell death/survival in a variety of cells and tissues. The elucidation of the mechanisms underlying strain-induced cell death and recovery from strain injury will facilitate our understanding of the pathogenesis of tendinopathy and may lead to the discovery of new molecular targets for early diagnosis and treatment of tendinopathy.

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The cytotoxic type 3 secretion system 1 ofVibriorewires host gene expression to subvert cell death and activate cell survival pathways

Science Signaling ◽

10.1126/scisignal.aal4501 ◽

2017 ◽

Vol 10 (479) ◽

pp. eaal4501 ◽

Cited By ~ 8

Author(s):

Nicole J. De Nisco ◽

Mohammed Kanchwala ◽

Peng Li ◽

Jessie Fernandez ◽

Chao Xing ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Cell Survival ◽

Secretion System ◽

Host Gene Expression ◽

Survival Pathways ◽

Type 3 Secretion System ◽

Activate Cell ◽

System 1 ◽

Type 3

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Aspects of Ovarian Function in a Line of Sheep with a Novel X-Linked Maternally-Imprinted Gene that is Associated with an Increased Ovulation Rate

10.26686/wgtn.16945789.v1 ◽

2021 ◽

Author(s):

◽

Elisabeth Sheinach Feary

Keyword(s):

Gene Expression ◽

Pituitary Gland ◽

Ovarian Function ◽

Follicular Development ◽

Cell Types ◽

Ovulation Rate ◽

Chromosome 2 ◽

Ovarian Follicular Development ◽

Er Alpha ◽

Large Ovary

<p>Fecundity is a term that refers to the number of offspring produced per female. It combines fertility (i.e. ability to produce offspring) and prolificacy (i.e. number of offspring). Ovulation rate i.e. the number of mature eggs released from the ovaries during one reproductive cycle in sheep, as with other mammals, is controlled by an exchange of hormonal signals between the pituitary gland and the ovary. Genetic mutations affecting ovulation are commonly referred to as the fecundity genes (Fec). The most obvious outcome is the number of offspring produced. There is already evidence of a number of major genes affecting the ovulation rate in sheep, specifically the Booroola, Inverdale, Hanna and more recently the Woodlands gene. The sheep carrying the Woodlands gene arose because the mutation was first recognised on a farm in Woodlands, Southland, New Zealand. Woodlands have a novel, X-linked maternally-imprinted, fecundity trait referred to as FecX2w, where Fec = fecundity, X = X chromosome, 2= 2nd mutation identified on X and W= Woodlands. The studies in this thesis investigated ovarian follicular development in both 4-week old Woodland carrier (W+) and non-carrier (++) lambs and adult ewes and evaluated some aspects of the endocrine interactions between the ovary and pituitary gland. The purpose was to identify potential physiological effects of the FecX2w gene on ovarian function. A confounding issue during these studies was the discovery that a large ovary phenotype (LOP) which was present in many of the W+ but not ++ lambs at 4 weeks of age was in fact a coincidence and not linked to the FecX2w mutation. The key findings from the studies of lambs and/or ewes that were carriers (W+) or non-carriers (++) of the FecX2w gene were: 1. No genotype differences were present either in the numbers of primordial (i.e. Type 1/1a follicles) or developing preantral (i.e. Types 2-4 follicles); 2. Significant genotype differences were present in the numbers of small antral (Type 5) follicles (W+>++; p<0.05); 3. An earlier onset of antral follicular development in W+ vs. ++ ewes with irregularities in morphology between the basement membrane and stroma in the former; 4. No genotype differences in the onset of gene expression during follicular development or in the cell-types expressing GDF9, BMP15, alpha inhibin, beta A inhibin and beta B inhibin, FSHR, ER alpha, or ER beta; 5. No genotype differences in the levels of GDF9 or BMP15 gene expression in oocytes throughout follicular growth; 6. No genotype difference in the diameters that follicles reached in W+ vs. ++ ewes; 7. Some lambs at 4-weeks of age had unusually large ovaries with an exceptional level of antral follicular development that is reminiscent of a polycystic ovarian condition. The underlying cause of this condition is unknown. In conclusion, the physiological characteristics of ovarian follicular development in ewes with the FecX2w gene is different from that in ewes with the Booroola, Inverdale, Hanna or other recently identified mutations.</p>

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Apoptosis of Dedifferentiated Hepatoma Cells is Independent of NF-κB Activation in Response to LPS

Bioscience Reports ◽

10.1007/s10540-007-9049-9 ◽

2007 ◽

Vol 27 (4-5) ◽

pp. 235-246

Author(s):

M. Ryan Reidy ◽

Janette Ellis ◽

Erin A. Schmitz ◽

David M. Kraus ◽

Gary A. Bulla

Keyword(s):

Gene Expression ◽

Cell Death ◽

Protein Synthesis ◽

Cell Survival ◽

Cell Types ◽

Hepatoma Cells ◽

Protein Synthesis Inhibitor ◽

Protein Synthesis Inhibitors ◽

Synthesis Inhibitor ◽

Dedifferentiated Hepatoma

Dedifferentiated hepatoma cells, in contrast to most other cell types including hepatoma cells, undergo apoptosis when treated with lipopolysaccharide (LPS) plus the protein synthesis inhibitor cycloheximide (CHx). We recently reported that the dedifferentiated hepatoma cells also exhibit a strong and prolonged NF-κB induction phenotype upon exposure to LPS, suggesting that NF-κB signaling may play a pro-survival role, as reported in several other cell systems. To test the role of NF-κB in preventing LPS-mediated apoptosis, we examined the dedifferentiated cell line M38. Results show that antioxidants strongly inhibited LPS + CHx-mediated cell death in the M38 cells, yet only modestly inhibited NF-κB induction. In addition, inhibition of NF-κB translocation by infection of the M38 cells with an adenoviral vector expressing an IκBα super-repressor did not result in LPS-mediated cell death. These results suggest that unlike TNFα induction, the cell survival pathway activated in response to LPS is independent of NF-κB translocation in the dedifferentiated cells. Addition of inhibitors of JNK, p38 and ERK pathways also failed to elicit LPS-mediated apoptosis similar to that observed when protein synthesis is prevented. Thus, cell survival pathways other than those involving NF-κB inducible gene expression or other well-known pathways appear to be involved in protecting the dedifferentiated hepatoma variant cells from LPS-mediated apoptosis. Importantly, this pro-apoptotic function of LPS appears to be a function of loss of hepatic gene expression, as the parental hepatoma cells resist LPS-mediated apoptosis in the presence of protein synthesis inhibitors.

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