scholarly journals CrossTORC and WNTegration in Disease: Focus on Lymphangioleiomyomatosis

2021 ◽  
Vol 22 (5) ◽  
pp. 2233
Author(s):  
Jilly Frances Evans ◽  
Kseniya Obraztsova ◽  
Susan M. Lin ◽  
Vera P. Krymskaya
Keyword(s):  
Integration Site ◽  
Cancer Development ◽  
Mechanistic Target Of Rapamycin ◽  
Complex Interactions ◽  
Signal Transduction Networks ◽  
Evolutionarily Conserved ◽  
Future Potential ◽  
Cellular Development ◽  
Wnt Signal ◽  
Disease Focus

The mechanistic target of rapamycin (mTOR) and wingless-related integration site (Wnt) signal transduction networks are evolutionarily conserved mammalian growth and cellular development networks. Most cells express many of the proteins in both pathways, and this review will briefly describe only the key proteins and their intra- and extracellular crosstalk. These complex interactions will be discussed in relation to cancer development, drug resistance, and stem cell exhaustion. This review will also highlight the tumor-suppressive tuberous sclerosis complex (TSC) mutated, mTOR-hyperactive lung disease of women, lymphangioleiomyomatosis (LAM). We will summarize recent advances in the targeting of these pathways by monotherapy or combination therapy, as well as future potential treatments.

scholarly journals Transcriptional Analysis of the Adeno-Associated Virus Integration Site

2009 ◽  
Vol 83 (23) ◽  
pp. 12512-12525 ◽  
Author(s):  
Nathalie Dutheil ◽  
Els Henckaerts ◽  
Erik Kohlbrenner ◽  
R. Michael Linden
Keyword(s):  
Transcriptional Activity ◽  
Integration Site ◽  
Regulatory Elements ◽  
Transcriptional Analysis ◽  
Start Codon ◽  
Adeno Associated Virus ◽  
Site Specific ◽  
Complex Interactions ◽  
Site Specific Integration ◽  
Virus Integration

ABSTRACT The nonpathogenic human adeno-associated virus type 2 (AAV-2) has adopted a unique mechanism to site-specifically integrate its genome into the human MBS85 gene, which is embedded in AAVS1 on chromosome 19. The fact that AAV has evolved to integrate into this ubiquitously transcribed region and that the chromosomal motifs required for integration are located a few nucleotides upstream of the translation initiation start codon of MBS85 suggests that the transcriptional activity of MBS85 might influence site-specific integration and thus might be involved in the evolution of this mechanism. In order to begin addressing this question, we initiated the characterization of the human MBS85 promoter region and compared its transcriptional activity to that of the AAV-2 p5 promoter. Our results clearly indicate that AAVS1 is defined by a complex transcriptional environment and that the MBS85 promoter shares key regulatory elements with the viral p5 promoter. Furthermore, we provide evidence for bidirectional MBS85 promoter activity and demonstrate that the minimal motifs required for AAV site-specific integration are present in the 5′ untranslated region of the gene and play a posttranscriptional role in the regulation of MBS85 expression. These findings should provide a framework to further elucidate the complex interactions between the virus and its cellular host in this unique pathway to latency.

Temporal and spatial expression of adrenomedullin and its receptors in the porcine uterus and peri-implantation conceptuses

2021 ◽  
Author(s):  
Sudikshya Paudel ◽  
Bangmin Liu ◽  
Magdalina J Cummings ◽  
Kelsey E Quinn ◽  
Fuller W Bazer ◽  
...  
Keyword(s):  
Peptide Hormone ◽  
Uterine Receptivity ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Uterine Fluid ◽  
Temporal And Spatial ◽  
Functional Peptide ◽  
And Migration ◽  
Implantation Period ◽  
Proliferation And Migration

Abstract Adrenomedullin (ADM) is an evolutionarily conserved multi-functional peptide hormone that regulates implantation, embryo spacing and placentation in humans and rodents. However, the potential roles of ADM in implantation and placentation in pigs, as a litter-bearing species, are not known. This study determined abundances of ADM in uterine luminal fluid, and the patterns of expression of ADM and its receptor components (CALCRL, RAMP2, RAMP3, and ACKR3) in uteri from cyclic and pregnant gilts, as well as conceptuses (embryonic/fetus and its extra-embryonic membranes) during the peri-implantation period of pregnancy. Total recoverable ADM was greater in the uterine fluid of pregnant compared with cyclic gilts between Days 10 and 16 post-estrus, and was from uterine luminal epithelial (LE) and conceptus trophectoderm (Tr) cells. Uterine expression of CALCRL, RAMP2, and ACKR3 were affected by day (P < 0.05), pregnant status (P < 0.01) and/or day x status (P < 0.05). Within porcine conceptuses, expression of CALCRL, RAMP2 and ACKR3 increased between Days 10 and 16 of pregnancy. Using an established porcine trophectoderm (pTr1) cell line, it was determined that 10−7 M ADM stimulated proliferation of pTr1 cells (P < 0.05) at 48 h, and increased phosphorylated mechanistic target of rapamycin (p-MTOR) and 4E binding protein 1 (p-4EBP1) by 6.1- and 4.9-fold (P < 0.0001), respectively. These novel results indicate a significant role for ADM in uterine receptivity for implantation and conceptus growth and development in pigs. They also provide a framework for future studies of ADM signaling to affect proliferation and migration of Tr cells, spacing of blastocysts, implantation and placentation in pigs.

scholarly journals Ras, PI3K and mTORC2 – three's a crowd?

2020 ◽  
Vol 133 (19) ◽  
pp. jcs234930
Author(s):  
Stephen F. Smith ◽  
Shannon E. Collins ◽  
Pascale G. Charest
Keyword(s):  
Ras Signaling ◽  
Cell Type ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Intracellular Compartments ◽  
Ras Effectors ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

ABSTRACTThe Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate – which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.

scholarly journals The Challenging Riddle about the Janus-Type Role of Hsp60 and Related Extracellular Vesicles and miRNAs in Carcinogenesis and the Promises of Its Solution

2021 ◽  
Vol 11 (3) ◽  
pp. 1175
Author(s):  
Sabrina David ◽  
Alessandra Maria Vitale ◽  
Alberto Fucarino ◽  
Federica Scalia ◽  
Giuseppe Vergilio ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Extracellular Vesicles ◽  
Cancer Development ◽  
Cancer Therapies ◽  
Ongoing Research ◽  
Pathological Conditions ◽  
Anti Cancer ◽  
Evolutionarily Conserved ◽  
The Impact

Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 also occurs in other locations, intracellularly and extracellularly, including cytosol, plasma-cell membrane, and extracellular vesicles (EVs). Consequently, non-canonical functions and interacting partners of Hsp60 have been identified and it has been realized that it is a hub molecule in diverse networks and pathways and that it is implicated, directly or indirectly, in the development of various pathological conditions, the Hsp60 chaperonopathies. In this review, we will focus on the multi-faceted role of this chaperonin in human cancers, showing the contribution of intra- and extracellular Hsp60 in cancer development and progression, as well as the impact of miRNA-mediated regulation of Hsp60 in carcinogenesis. There are still various aspects of this intricate biological scenario that are poorly understood but ongoing research is steadily providing new insights and we will direct attention to them. For instance, we will highlight the possible applications of the Hsp60 involvement in carcinogenesis not only in diagnosis, but also in the development of specific anti-cancer therapies centered on the use of the chaperonin as therapeutic target or agent and depending on its role, pro- or anti-tumor.

scholarly journals DEPTOR in Skeletal Development and Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Jose Miguel Perez-Tejeiro ◽  
Fabiana Csukasi
Keyword(s):  
Skeletal Development ◽  
Negative Regulator ◽  
Current Understanding ◽  
Skeletal Biology ◽  
Interacting Protein ◽  
Cellular Processes ◽  
The Past ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Important Regulator

Discovered in 2009, the DEP-domain containing mTOR-interacting protein, DEPTOR, is a known regulator of the mechanistic target of rapamycin (mTOR), an evolutionarily conserved kinase that regulates diverse cellular processes in response to environmental stimuli. DEPTOR was originally identified as a negative regulator of mTOR complexes 1 (mTORC1) and 2 (mTORC2). However, recent discoveries have started to unravel the roles of DEPTOR in mTOR-independent responses. In the past few years, mTOR emerged as an important regulator of skeletal development, growth, and homeostasis; the dysregulation of its activity contributes to the development of several skeletal diseases, both chronic and genetic. Even more recently, several groups have reported on the relevance of DEPTOR in skeletal biology through its action on mTOR-dependent and mTOR-independent pathways. In this review, we summarize the current understanding of DEPTOR in skeletal development and disease.

pygopusencodes a nuclear protein essential for Wingless/Wnt signaling

Development ◽  
2002 ◽  
Vol 129 (17) ◽  
pp. 4089-4101 ◽  
Author(s):  
Tatyana Y. Belenkaya ◽  
Chun Han ◽  
Henrietta J. Standley ◽  
Xinda Lin ◽  
Douglas W. Houston ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Target Genes ◽  
Nuclear Protein ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Phd Finger ◽  
Nuclear Function ◽  
Evolutionarily Conserved ◽  
Wnt Signal

The Wingless (Wg)/Wnt signal transduction pathway regulates many developmental processes through a complex of Armadillo(Arm)/β-catenin and the HMG-box transcription factors of the Tcf family. We report the identification of a new component, Pygopus (Pygo), that plays an essential role in the Wg/Wnt signal transduction pathway. We show that Wg signaling is diminished during embryogenesis and imaginal disc development in the absence of pygo activity. Pygo acts downstream or in parallel with Arm to regulate the nuclear function of Arm protein. pygo encodes a novel and evolutionarily conserved nuclear protein bearing a PHD finger that is essential for its activity. We further show that Pygo can form a complex with Arm in vivo and possesses a transcription activation domain(s). Finally, we have isolated a Xenopus homolog of pygo (Xpygo). Depletion of maternal Xpygo by antisense deoxyoligonucleotides leads to ventralized embryonic defects and a reduction of the expression of Wnt target genes. Together, these findings demonstrate that Pygo is an essential component in the Wg/Wnt signal transduction pathway and is likely to act as a transcription co-activator required for the nuclear function of Arm/β-catenin.

scholarly journals Role of Microbiome in Modulating Immune Responses in Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Mukulika Bose ◽  
Pinku Mukherjee
Keyword(s):  
Environmental Factors ◽  
Immune Responses ◽  
Disease Susceptibility ◽  
Cancer Susceptibility ◽  
Cancer Development ◽  
Complex Interactions ◽  
Gene Environment ◽  
Mechanisms Of Carcinogenesis ◽  
Insight Into

The complex interactions between genes and the environment play important roles in disease susceptibility and progression. One of the chronic diseases that is affected by this gene-environment interplay is cancer. However, our knowledge about these environmental factors remains limited. The microorganisms that inhabit our bodies have recently been acknowledged to play a crucial role as an environmental factor, to which we are constantly exposed. Studies have revealed significant differences in the relative abundance of certain microbes in cancer cases compared with controls. It has been reported that changes in the composition of normal gut microbiota can increase/decrease cancer susceptibility and progression by diverse mechanisms including, but not limited to, inflammation—a well-known hallmark of carcinogenesis. The microbiota can also affect the response to various treatments including immunotherapy. The microbiome-immune-cancer axis will continue to provide insight into the basic mechanisms of carcinogenesis. In this review, we provide a brief understanding of the mechanisms by which microbiota affects cancer development, progression, and treatment.

scholarly journals Mapping Transgene Insertion Sites Reveals Complex Interactions Between Mouse Transgenes and Neighboring Endogenous Genes

2018 ◽  
Author(s):  
Mallory A. Laboulaye ◽  
Xin Duan ◽  
Mu Qiao ◽  
Irene E. Whitney ◽  
Joshua R. Sanes
Keyword(s):  
Integration Site ◽  
Insertion Site ◽  
Cell Types ◽  
Regulatory Elements ◽  
Endogenous Gene ◽  
Complex Interactions ◽  
Distinct Cell ◽  
Transgenic Lines ◽  
Endogenous Genes ◽  
Insertion Sites

ABSTRACTTransgenic mouse lines are routinely employed to label and manipulate distinct cell types. The transgene generally comprises cell-type specific regulatory elements linked to a cDNA encoding a reporter or other proteins. However, off-target expression seemingly unrelated to the regulatory elements in the transgene is often observed, and sometimes suspected to reflect influences related to the site of transgene integration in the genome. To test this hypothesis, we used a proximity ligation-based method, Targeted Locus Amplification (TLA), to map the insertion sites of three well-characterized transgenes that appeared to exhibit insertion site-dependent expression in retina. The nearest endogenous genes to transgenes HB9-GFP, Mito-P, and TYW3 are Cdh6, Fat4 and Khdrbs2, respectively. For two lines, we demonstrate that expression reflects that of the closest endogenous gene (Fat4 and Cdh6), even though the distance between transgene and endogenous gene is 550 and 680 kb, respectively. In all three lines, the transgenes decrease expression of the neighboring endogenous genes. In each case, the affected endogenous gene was expressed in at least some of the cell types that the transgenic line has been used to mark and study. These results provide insights into the effects of transgenes and endogenous genes on each other’s expression, demonstrate that mapping insertion site is valuable for interpreting results obtained with transgenic lines, and indicate that TLA is a reliable method for integration site discovery.

scholarly journals mTORC1-chaperonin CCT signaling regulates m6A RNA methylation to suppress autophagy

2021 ◽  
Vol 118 (10) ◽  
pp. e2021945118 ◽  
Author(s):  
Hong-Wen Tang ◽  
Jui-Hsia Weng ◽  
Wen Xing Lee ◽  
Yanhui Hu ◽  
Lei Gu ◽  
...  
Keyword(s):  
Cellular Responses ◽  
Environmental Cues ◽  
Messenger Rnas ◽  
Rna Methylation ◽  
Mechanistic Target Of Rapamycin ◽  
Downstream Effector ◽  
Mtorc1 Signaling ◽  
Evolutionarily Conserved ◽  
Rna Biogenesis ◽  
M6a Rna Methylation

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a central regulator of cell growth and metabolism that senses and integrates nutritional and environmental cues with cellular responses. Recent studies have revealed critical roles of mTORC1 in RNA biogenesis and processing. Here, we find that the m6A methyltransferase complex (MTC) is a downstream effector of mTORC1 during autophagy in Drosophila and human cells. Furthermore, we show that the Chaperonin Containing Tailless complex polypeptide 1 (CCT) complex, which facilitates protein folding, acts as a link between mTORC1 and MTC. The mTORC1 activates the chaperonin CCT complex to stabilize MTC, thereby increasing m6A levels on the messenger RNAs encoding autophagy-related genes, leading to their degradation and suppression of autophagy. Altogether, our study reveals an evolutionarily conserved mechanism linking mTORC1 signaling with m6A RNA methylation and demonstrates their roles in suppressing autophagy.

Where’s the fat? Freeze-fracture analysis of ingredient interactions in food systems

1993 ◽  
Vol 51 ◽  
pp. 48-49
Author(s):  
Jean Fincher
Keyword(s):  
Lipid Droplets ◽  
Food Systems ◽  
Food Industry ◽  
Freeze Fracture ◽  
Food Science ◽  
Complex Interactions ◽  
Fat Reduction ◽  
Important Trend ◽  
Conventional Foods ◽  
Whipped Cream

An important trend in the food industry today is reduction in the amount of fat in manufactured foods. Often fat reduction is accomplished by replacing part of the natural fat with carbohydrates which serve to bind water and increase viscosity. It is in understanding the roles of these two major components of food, fats and carbohydrates, that freeze-fracture is so important. It is well known that conventional fixation procedures are inadequate for many food products, in particular, foods with carbohydrates as a predominant structural feature. For some food science applications the advantages of freeze-fracture preparation procedures include not only the avoidance of chemical fixatives, but also the opportunity to control the temperature of the sample just prior to rapid freezing.In conventional foods freeze-fracture has been used most successfully in analysis of milk and milk products. Milk gels depend on interactions between lipid droplets and proteins. Whipped emulsions, either whipped cream or ice cream, involve complex interactions between lipid, protein, air cell surfaces, and added emulsifiers.

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