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Article ; Online: The Musashi RNA binding proteins direct the translational activation of key pituitary mRNAs.

Banik, Jewel / Moreira, Ana Rita Silva / Lim, Juchan / Tomlinson, Sophia / Hardy, Linda L / Lagasse, Alex / Haney, Anessa / Crimmins, Meghan R / Boehm, Ulrich / Odle, Angela K / MacNicol, Melanie C / Childs, Gwen V / MacNicol, Angus M

Scientific reports

2024 Volume 14, Issue 1, Page(s) 5918

Abstract: The pituitary functions as a master endocrine gland that secretes hormones critical for regulation of a wide variety of physiological processes including reproduction, growth, metabolism and stress responses. The distinct hormone-producing cell lineages ... ...

Abstract	The pituitary functions as a master endocrine gland that secretes hormones critical for regulation of a wide variety of physiological processes including reproduction, growth, metabolism and stress responses. The distinct hormone-producing cell lineages within the pituitary display remarkable levels of cell plasticity that allow remodeling of the relative proportions of each hormone-producing cell population to meet organismal demands. The molecular mechanisms governing pituitary cell plasticity have not been fully elucidated. Our recent studies have implicated a role for the Musashi family of sequence-specific mRNA binding proteins in the control of pituitary hormone production, pituitary responses to hypothalamic stimulation and modulation of pituitary transcription factor expression in response to leptin signaling. To date, these actions of Musashi in the pituitary appear to be mediated through translational repression of the target mRNAs. Here, we report Musashi1 directs the translational activation, rather than repression, of the Prop1, Gata2 and Nr5a1 mRNAs which encode key pituitary lineage specification factors. We observe that Musashi1 further directs the translational activation of the mRNA encoding the glycolipid Neuronatin (Nnat) as determined both in mRNA reporter assays as well as in vivo. Our findings suggest a complex bifunctional role for Musashi1 in the control of pituitary cell function.
MeSH term(s)	RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/metabolism ; Pituitary Gland/metabolism ; Protein Processing, Post-Translational ; Pituitary Hormones/metabolism
Chemical Substances	RNA, Messenger ; RNA-Binding Proteins ; Pituitary Hormones
Language	English
Publishing date	2024-03-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-56002-8
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Article: Molecular Mechanisms of Pituitary Cell Plasticity.

Childs, Gwen V / MacNicol, Angus M / MacNicol, Melanie C

Frontiers in endocrinology

2020 Volume 11, Page(s) 656

Abstract: The mechanisms that mediate plasticity in pituitary function have long been a subject of vigorous investigation. Early studies overcame technical barriers and challenged conceptual barriers to identify multipotential and multihormonal cell populations ... ...

Abstract	The mechanisms that mediate plasticity in pituitary function have long been a subject of vigorous investigation. Early studies overcame technical barriers and challenged conceptual barriers to identify multipotential and multihormonal cell populations that contribute to diverse pituitary stress responses. Decades of intensive study have challenged the standard model of dedicated, cell type-specific hormone production and have revealed the malleable cellular fates that mediate pituitary responses. Ongoing studies at all levels, from animal physiology to molecular analyses, are identifying the mechanisms underlying this cellular plasticity. This review describes the findings from these studies that utilized state-of-the-art tools and techniques to identify mechanisms of plasticity throughout the pituitary and focuses on the insights brought to our understanding of pituitary function.
MeSH term(s)	Animals ; Cell Plasticity ; Endocrine System/physiology ; Humans ; Pituitary Gland/physiology ; Signal Transduction
Language	English
Publishing date	2020-09-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2020.00656
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Article ; Online: Post-Transcriptional Regulation of

Odle, Angela K / MacNicol, Melanie C / Childs, Gwen V / MacNicol, Angus M

International journal of molecular sciences

2021 Volume 22, Issue 7

Abstract: The proper expression of gonadotropin-releasing hormone receptors (GnRHRs) by pituitary gonadotropes is critical for maintaining maximum reproductive capacity. GnRH receptor expression must be tightly regulated in order to maintain the normal pattern of ... ...

Abstract	The proper expression of gonadotropin-releasing hormone receptors (GnRHRs) by pituitary gonadotropes is critical for maintaining maximum reproductive capacity. GnRH receptor expression must be tightly regulated in order to maintain the normal pattern of expression through the estrous cycle in rodents, which is believed to be important for interpreting the finely tuned pulses of GnRH from the hypothalamus. Much work has shown that
MeSH term(s)	3' Untranslated Regions ; Adipokines/metabolism ; Animals ; Estrus ; Female ; Gene Expression Regulation ; Gonadotropin-Releasing Hormone/metabolism ; Humans ; Hypothalamus/metabolism ; Leptin/metabolism ; Mice ; Pituitary Gland/metabolism ; RNA, Messenger/metabolism ; Rats ; Receptors, LHRH/genetics ; Receptors, LHRH/metabolism ; Reproduction ; Transcription, Genetic
Chemical Substances	3' Untranslated Regions ; Adipokines ; GNRHR protein, human ; Leptin ; RNA, Messenger ; Receptors, LHRH ; Gonadotropin-Releasing Hormone (33515-09-2)
Language	English
Publishing date	2021-03-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22073312
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Article ; Online: The Importance of Leptin to Reproduction.

Childs, Gwen V / Odle, Angela K / MacNicol, Melanie C / MacNicol, Angus M

Endocrinology

2020 Volume 162, Issue 2

Abstract: A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is ... ...

Abstract	A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.
MeSH term(s)	Adipocytes/metabolism ; Animals ; Female ; Humans ; Hypothalamo-Hypophyseal System/metabolism ; Leptin/physiology ; Male ; Ovary/metabolism ; Reproduction ; Signal Transduction ; Testis/metabolism
Chemical Substances	Leptin
Language	English
Publishing date	2020-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqaa204
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Article ; Online: Post-Transcriptional Regulation of Gnrhr

Angela K. Odle / Melanie C. MacNicol / Gwen V. Childs / Angus M. MacNicol

International Journal of Molecular Sciences, Vol 22, Iss 3312, p

A Checkpoint for Metabolic Control of Female Reproduction

2021 Volume 3312

Abstract	The proper expression of gonadotropin-releasing hormone receptors (GnRHRs) by pituitary gonadotropes is critical for maintaining maximum reproductive capacity. GnRH receptor expression must be tightly regulated in order to maintain the normal pattern of expression through the estrous cycle in rodents, which is believed to be important for interpreting the finely tuned pulses of GnRH from the hypothalamus. Much work has shown that Gnrhr expression is heavily regulated at the level of transcription. However, researchers have also discovered that Gnrhr is regulated post-transcriptionally. This review will discuss how RNA-binding proteins and microRNAs may play critical roles in the regulation of GnRHR expression. We will also discuss how these post-transcriptional regulators may themselves be affected by metabolic cues, specifically with regards to the adipokine leptin. All together, we present evidence that Gnrhr is regulated post-transcriptionally, and that this concept must be further explored in order to fully understand the complex nature of this receptor.
Keywords	gonadotropin-releasing hormone receptor ; post-transcriptional control ; leptin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Anterior Pituitary Transcriptomics Following a High-Fat Diet: Impact of Oxidative Stress on Cell Metabolism.

Miles, Tiffany K / Odle, Angela K / Byrum, Stephanie D / Lagasse, Alex / Haney, Anessa / Ortega, Victoria G / Bolen, Cole R / Banik, Jewel / Reddick, Milla M / Herdman, Ashley / MacNicol, Melanie C / MacNicol, Angus M / Childs, Gwen V

Endocrinology

2023 Volume 165, Issue 2

Abstract: Anterior pituitary cell function requires a high level of protein synthesis and secretion which depend heavily on mitochondrial adenosine triphosphate production and functional endoplasmic reticula. Obesity adds stress to tissues, requiring them to adapt ...

Abstract	Anterior pituitary cell function requires a high level of protein synthesis and secretion which depend heavily on mitochondrial adenosine triphosphate production and functional endoplasmic reticula. Obesity adds stress to tissues, requiring them to adapt to inflammation and oxidative stress, and adding to their allostatic load. We hypothesized that pituitary function is vulnerable to the stress of obesity. Here, we utilized a 10- to 15-week high-fat diet (HFD, 60%) in a thermoneutral environment to promote obesity, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-sequencing analysis. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin and decreases in adiponectin. HFD caused increased inflammatory markers: interleukin-6, resistin, monocyte chemoattractant protein-1, and tumor necrosis factorα. HFD males and females also had increased insulin and increased TSH, and HFD females had decreased serum prolactin and growth hormone pulse amplitude. Pituitary single-cell transcriptomics revealed modest or no changes in pituitary cell gene expression from HFD males after 10 or 15 weeks or from HFD females after 10 weeks. However, HFD females (15 weeks) showed significant numbers of differentially expressed genes in lactotropes and pituitary stem cells. Collectively, these studies reveal that pituitary cells from males appear to be more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females.
MeSH term(s)	Male ; Female ; Mice ; Animals ; Diet, High-Fat/adverse effects ; Obesity/metabolism ; Weight Gain ; Gene Expression Profiling ; Oxidative Stress ; Mice, Inbred C57BL
Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqad191
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Article ; Online: Musashi Exerts Control of Gonadotrope Target mRNA Translation During the Mouse Estrous Cycle.

Endocrinology

2023 Volume 164, Issue 9

Abstract: The anterior pituitary controls key biological processes, including growth, metabolism, reproduction, and stress responses through distinct cell types that each secrete specific hormones. The anterior pituitary cells show a remarkable level of cell type ... ...

Abstract	The anterior pituitary controls key biological processes, including growth, metabolism, reproduction, and stress responses through distinct cell types that each secrete specific hormones. The anterior pituitary cells show a remarkable level of cell type plasticity that mediates the shifts in hormone-producing cell populations that are required to meet organismal needs. The molecular mechanisms underlying pituitary cell plasticity are not well understood. Recent work has implicated the pituitary stem cell populations and specifically, the mRNA binding proteins of the Musashi family in control of pituitary cell type identity. In this study we have identified the target mRNAs that mediate Musashi function in the adult mouse pituitary and demonstrate the requirement for Musashi function in vivo. Using Musashi RNA immunoprecipitation, we identify a cohort of 1184 mRNAs that show specific Musashi binding. Identified Musashi targets include the Gnrhr mRNA, which encodes the gonadotropin-releasing hormone receptor (GnRHR), and the Fshb mRNA, encoding follicle-stimulating hormone (FSH). Reporter assays reveal that Musashi functions to exert repression of translation of the Fshb mRNA, in addition to the previously observed repression of the Gnrhr mRNA. Importantly, mice engineered to lack Musashi in gonadotropes demonstrate a failure to repress translation of the endogenous Gnrhr and Fshb mRNAs during the estrous cycle and display a significant heterogeneity in litter sizes. The range of identified target mRNAs suggests that, in addition to these key gonadotrope proteins, Musashi may exert broad regulatory control over the pituitary proteome in a cell type-specific manner.
MeSH term(s)	Mice ; Animals ; Gonadotrophs/metabolism ; Follicle Stimulating Hormone/metabolism ; Carrier Proteins/metabolism ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Follicle Stimulating Hormone (9002-68-0) ; Carrier Proteins ; RNA, Messenger
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqad113
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Article ; Online: Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models.

Urbaniak, Alicja / Reed, Megan R / Fil, Daniel / Moorjani, Anika / Heflin, Sarah / Antoszczak, Michał / Sulik, Michał / Huczyński, Adam / Kupsik, Michalina / Eoff, Robert L / MacNicol, Melanie C / Chambers, Timothy C / MacNicol, Angus M

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2021 Volume 141, Page(s) 111815

Abstract: Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and ... ...

Abstract	Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC
MeSH term(s)	Antibiotics, Antineoplastic/chemical synthesis ; Antibiotics, Antineoplastic/pharmacology ; Breast Neoplasms/drug therapy ; CD24 Antigen ; Cell Division/drug effects ; Cell Line, Tumor ; Cell Movement ; Drug Discovery ; Drug Screening Assays, Antitumor ; Female ; Humans ; Hyaluronan Receptors/metabolism ; MCF-7 Cells ; Neoplastic Stem Cells/drug effects ; Pyrans/chemical synthesis ; Pyrans/pharmacology
Chemical Substances	Antibiotics, Antineoplastic ; CD24 Antigen ; Hyaluronan Receptors ; Pyrans ; salinomycin (62UXS86T64)
Language	English
Publishing date	2021-06-12
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2021.111815
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Article ; Online: Sex differences in somatotrope response to fasting: biphasic responses in male mice.

Miles, Tiffany K / Silva Moreira, Ana Rita / Allensworth-James, Melody L / Odle, Angela K / Haney, Anessa C / MacNicol, Angus M / MacNicol, Melanie C / Childs, Gwen V

The Journal of endocrinology

2020 Volume 247, Issue 3, Page(s) 213–224

Abstract: Anterior pituitary somatotropes are important metabolic sensors responding to leptin by secreting growth hormone (GH). However, reduced leptin signals caused by fasting have not always correlated with reduced serum GH. Reports show that fasting may ... ...

Abstract	Anterior pituitary somatotropes are important metabolic sensors responding to leptin by secreting growth hormone (GH). However, reduced leptin signals caused by fasting have not always correlated with reduced serum GH. Reports show that fasting may stimulate or reduce GH secretion, depending on the species. Mechanisms underlying these distinct somatotrope responses to fasting remain unknown. To define the somatotrope response to decreased leptin signaling we examined markers of somatotrope function over different time periods of fasting. Male mice were fasted for 24 and 48 h, with female mice fasted for 24 h compared to fed controls ad libitum. Body weight and serum glucose were reduced in both males and females, but, unexpectedly, serum leptin was reduced only in males. Furthermore, in males, serum GH levels showed a biphasic response with significant reductions at 24 h followed by a significant rise at 48 h, which coincided with the rise in serum ghrelin levels. In contrast, females showed an increase in serum GH at 24 h. We then explored mechanisms underlying the differential somatotrope responses seen in males and observed that pituitary levels of Gh mRNA increased, with no distinction between acute and prolonged fasting. By contrast, the Ghrhr mRNA (encoding GH releasing hormone receptor) and the Ghsr mRNA (encoding the ghrelin receptor) were both greatly increased at prolonged fasting times coincident with increased serum GH. These findings show sex differences in the somatotrope and adipocyte responses to fasting and support an adaptive role for somatotropes in males in response to multiple metabolic signals.
MeSH term(s)	Animals ; Fasting/metabolism ; Female ; Ghrelin/blood ; Growth Hormone/blood ; Growth Hormone-Releasing Hormone/genetics ; Growth Hormone-Releasing Hormone/metabolism ; Leptin/blood ; Male ; Mice ; Pituitary Gland, Anterior/metabolism ; Receptors, Ghrelin/genetics ; Receptors, Ghrelin/metabolism ; Sex Factors
Chemical Substances	Ghrelin ; Leptin ; Receptors, Ghrelin ; Growth Hormone (9002-72-6) ; Growth Hormone-Releasing Hormone (9034-39-3)
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-20-0275
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Article ; Online: Autoregulation of Musashi1 mRNA translation during Xenopus oocyte maturation.

Arumugam, Karthik / Macnicol, Melanie C / Macnicol, Angus M

Molecular reproduction and development

2012 Volume 79, Issue 8, Page(s) 553–563

Abstract: The mRNA translational control protein, Musashi, plays a critical role in cell fate determination through sequence-specific interactions with select target mRNAs. In proliferating stem cells, Musashi exerts repression of target mRNAs to promote cell ... ...

Abstract	The mRNA translational control protein, Musashi, plays a critical role in cell fate determination through sequence-specific interactions with select target mRNAs. In proliferating stem cells, Musashi exerts repression of target mRNAs to promote cell cycle progression. During stem cell differentiation, Musashi target mRNAs are de-repressed and translated. Recently, we have reported an obligatory requirement for Musashi to direct translational activation of target mRNAs during Xenopus oocyte meiotic cell cycle progression. Despite the importance of Musashi in cell cycle regulation, only a few target mRNAs have been fully characterized. In this study, we report the identification and characterization of a new Musashi target mRNA in Xenopus oocytes. We demonstrate that progesterone-stimulated translational activation of the Xenopus Musashi1 mRNA is regulated through a functional Musashi binding element (MBE) in the Musashi1 mRNA 3' untranslated region (3' UTR). Mutational disruption of the MBE prevented translational activation of Musashi1 mRNA and its interaction with Musashi protein. Further, elimination of Musashi function through microinjection of inhibitory antisense oligonucleotides prevented progesterone-induced polyadenylation and translation of the endogenous Musashi1 mRNA. Thus, Xenopus Musashi proteins regulate translation of the Musashi1 mRNA during oocyte maturation. Our results indicate that the hierarchy of sequential and dependent mRNA translational control programs involved in directing progression through meiosis are reinforced by an intricate series of nested, positive feedback loops, including Musashi mRNA translational autoregulation. These autoregulatory positive feedback loops serve to amplify a weak initiating signal into a robust commitment for the oocyte to progress through the cell cycle and become competent for fertilization.
MeSH term(s)	3' Untranslated Regions/physiology ; Animals ; Cell Cycle/drug effects ; Cell Cycle/physiology ; Female ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Oligonucleotides, Antisense/pharmacokinetics ; Oocytes/cytology ; Oocytes/metabolism ; Peptide Chain Initiation, Translational/physiology ; Polyadenylation/drug effects ; Polyadenylation/physiology ; Progesterone/pharmacology ; Progestins/pharmacology ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins ; Xenopus Proteins/genetics ; Xenopus Proteins/metabolism ; Xenopus laevis
Chemical Substances	3' Untranslated Regions ; Nerve Tissue Proteins ; Oligonucleotides, Antisense ; Progestins ; RNA-Binding Proteins ; Ribonucleoproteins ; Xenopus Proteins ; Msi1 protein, Xenopus (132866-76-3) ; Progesterone (4G7DS2Q64Y)
Language	English
Publishing date	2012-07-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	20321-x
ISSN	1098-2795 ; 1040-452X
ISSN (online)	1098-2795
ISSN	1040-452X
DOI	10.1002/mrd.22060
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