Long Glucocorticoid-induced Leucine Zipper (L-GILZ) Protein Interacts with Ras Protein Pathway and Contributes to Spermatogenesis Control

Bruscoli, Stefano; Velardi, Enrico; Sante, Moises Di; Bereshchenko, Oxana; Venanzi, Alessandra; Coppo, Maddalena; Berno, Valeria; Mameli, Maria Grazia; Colella, Renato; Cavaliere, Antonio; Riccardi, Carlo

doi:10.1074/jbc.m111.316372

Cited by 68 publications

(94 citation statements)

References 51 publications

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“…A few weeks after birth, hemizygous Tsc22d3 knockout males display Sertoli‐cell‐only seminiferous tubuli, which are totally devoid of germ cells. Importantly, wild‐type germ cells transplanted into the testes of hemizygous Tsc22d3 knockout males can repopulate seminiferous tubuli (Bruscoli et al ., 2012), suggesting that these testes can still support normal spermatogenesis. We thus reasoned that the testicular environment of hemizygous Tsc22d3 knockout males should be conducive to germ cell differentiation of cells that descended from the injected ES cells.…”

Section: Resultsmentioning

confidence: 99%

“…Our extensive validation has not revealed any evidence of leakiness, that is, of hemizygous Tsc22d3 knockout germ cells producing fertile spermatozoa; the sterility is due to a cell‐autonomous defect in spermatogenesis that is extremely stringent. In independent observations, males carrying one of three distinct Tsc22d3 knockout alleles were reported to be sterile (Bruscoli et al ., 2012; Ngo et al, 2013b; Romero et al ., 2012; Suarez et al ., 2012), consistent with a complete loss of the germline due to an intrinsic failure. Wild‐type germ cells transplanted into the testes of hemizygous Tsc22d3 knockout males can repopulate seminiferous tubuli (Bruscoli et al ., 2012), suggesting that these testes can still support normal spermatogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…In independent observations, males carrying one of three distinct Tsc22d3 knockout alleles were reported to be sterile (Bruscoli et al ., 2012; Ngo et al, 2013b; Romero et al ., 2012; Suarez et al ., 2012), consistent with a complete loss of the germline due to an intrinsic failure. Wild‐type germ cells transplanted into the testes of hemizygous Tsc22d3 knockout males can repopulate seminiferous tubuli (Bruscoli et al ., 2012), suggesting that these testes can still support normal spermatogenesis. Thus, the testicular environment of hemizygous Tsc22d3 knockout males and of chimeric males developing from injected goGermline blastocysts is conducive to germ cell differentiation, either from transplanted germ cells (Bruscoli et al ., 2012) or from germ cells that descended from the injected ES cells (this article).…”

Section: Discussionmentioning

confidence: 99%

“…Wild‐type germ cells transplanted into the testes of hemizygous Tsc22d3 knockout males can repopulate seminiferous tubuli (Bruscoli et al ., 2012), suggesting that these testes can still support normal spermatogenesis. Thus, the testicular environment of hemizygous Tsc22d3 knockout males and of chimeric males developing from injected goGermline blastocysts is conducive to germ cell differentiation, either from transplanted germ cells (Bruscoli et al ., 2012) or from germ cells that descended from the injected ES cells (this article). Although there is no reason to doubt the fidelity of sterility, it is cautious to rely on coat color differences when generating chimeras and assessing offspring, if only as quality control for mouse colony management and strain purity.…”

Section: Discussionmentioning

confidence: 99%

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Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Köentgen¹,

Lin

Κατίδου

et al. 2016

Genesis

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SummaryGene targeting in embryonic stem (ES) cells remains best practice for introducing complex mutations into the mouse germline. One aspect in this multistep process that has not been streamlined with regard to the logistics and ethics of mouse breeding is the efficiency of germline transmission: the transmission of the ES cell‐derived genome through the germline of chimeras to their offspring. A method whereby male chimeras transmit exclusively the genome of the injected ES cells to their offspring has been developed. The new technology, referred to as goGermline, entails injecting ES cells into blastocysts produced by superovulated homozygous Tsc22d3 floxed females mated with homozygous ROSA26‐Cre males. This cross produces males that are sterile due to a complete cell‐autonomous defect in spermatogenesis. The resulting male chimeras can be sterile but when fertile, they transmit the ES cell‐derived genome to 100% of their offspring. The method was validated extensively and in two laboratories for gene‐targeted ES clones that were derived from the commonly used parental ES cell lines Bruce4, E14, and JM8A3. The complete elimination of the collateral birth of undesired, non‐ES cell‐derived offspring in goGermline technology fulfills the reduction imperative of the 3R principle of humane experimental technique with animals. genesis 54:326–333, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Köentgen¹,

Lin

Κατίδου

et al. 2016

Genesis

View full text Add to dashboard Cite

show abstract

“…[18][19][20][21][22][23] GILZ and L-GILZ bind Ras and contribute to cell differentiation and the control of tumorigenesis. 24,25 Crosstalk between p53 and GCs has been described as either antagonistic or synergistic depending on cell type and environmental context. 26 Some reports suggest that p53 activation is not necessary for GC-induced apoptotic cell death 27 but may instead increase resistance to GC therapy.…”

mentioning

confidence: 99%

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

et al. 2014

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The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53 þ / þ HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53 þ / þ cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation.

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Divergent Effects of Endogenous and Exogenous Glucocorticoid‐Induced Leucine Zipper in Animal Models of Inflammation and Arthritis

Ngo

Beaulieu

et al. 2013

Arthritis & Rheumatism

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Objective. Glucocorticoid-induced leucine zipper (GILZ) has effects on inflammatory pathways that suggest it to be a key inhibitory regulator of the immune system, and its expression is exquisitely sensitive to induction by glucocorticoids. We undertook this study to test our hypothesis that GILZ deficiency would exacerbate experimental immune-mediated inflammation and impair the effects of glucocorticoids on inflammation and, correspondingly, that exogenous GILZ would inhibit these events.Methods. GILZ ؊/؊ mice were generated using the Cre/loxP system, and responses were studied in delayedtype hypersensitivity (DTH), antigen-induced arthritis (AIA), K/BxN serum-transfer arthritis, and lipopolysaccharide (LPS)-induced cytokinemia. Therapeutic expression of GILZ via administration of recombinant adeno-associated virus expressing the GILZ gene (GILZ-rAAV) was compared to the effects of glucocorticoid in collagen-induced arthritis (CIA).Results. Increased T cell proliferation and DTH were observed in GILZ ؊/؊ mice, but neither AIA nor K/BxN serum-transfer arthritis was affected, and GILZ deficiency did not affect LPS-induced cytokinemia. Deletion of GILZ did not impair the effects of exogenous glucocorticoids on CIA or cytokinemia. In contrast, overexpression of GILZ in joints significantly inhibited CIA, with an effect similar to that of dexamethasone. Conclusion. Despite effects on T cell activation, GILZ deficiency had no effect on effector pathways of arthritis and was unexpectedly redundant with effects of glucocorticoids. These findings do not support the hypothesis that GILZ is central to the actions of glucocorticoids, but the efficacy of exogenous GILZ in CIA suggests that further evaluation of GILZ in inflammatory disease is required.

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Long Glucocorticoid-induced Leucine Zipper (L-GILZ) Protein Interacts with Ras Protein Pathway and Contributes to Spermatogenesis Control

Cited by 68 publications

References 51 publications

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

Divergent Effects of Endogenous and Exogenous Glucocorticoid‐Induced Leucine Zipper in Animal Models of Inflammation and Arthritis

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