scholarly journals The blended phenotype of a germline RIT1 and a mosaic PIK3CA variant

2021 ◽  
Vol 7 (6) ◽  
pp. a006121
Author(s):  
Siren Berland ◽  
Jørgen Jareld ◽  
Nicholas Hickson ◽  
Helene Schlecht ◽  
Gunnar Houge ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cellular Stress ◽  
Targeted Sequencing ◽  
Gain Of Function ◽  
Somatic Variant ◽  
Malformation Syndrome ◽  
Chance Event ◽  
Apoptotic Effect ◽  
A Cell ◽  
Growth Promoting

We report a patient with a germline RIT1 and a mosaic PIK3CA variant. The diagnosis of the RASopathy was confirmed by targeted sequencing following the identification of transient cardiomyopathy in a patient with PIK3CA-related overgrowth spectrum (PROS). Our observation confirms that the PIK3CA gain-of-function (GoF) variant effects dominate those of the RASopathy, and the resulting blended phenotype mostly resembles megalencephaly-capillary malformation syndrome (MCAP PROS). There appears to be interaction between RIT1 and PI3K-AKT because the latter pathway is needed for the growth-promoting activity of the first, at least in adenocarcinomas, but the details of this interaction are not known. If so, the PIK3CA somatic variant may not be just a chance event. It could also be of etiological relevance that Rit activation mediates resistance to cellular stress—that is, promotes cell survival. This anti-apoptotic effect could also make it more likely that a cell that spontaneously acquires a PIK3CA GoF variant will survive and proliferate. We aim to encourage clinicians to investigate atypical findings in individuals with PROS. If further similar cases are reported, this would suggest that the establishment of PROS mosaicism is facilitated by the background of a RASopathy.

scholarly journals Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

2021 ◽  
Vol 22 (2) ◽  
pp. 817
Author(s):  
Junfang Yan ◽  
Yi Xie ◽  
Jing Si ◽  
Lu Gan ◽  
Hongyan Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Survival ◽  
Cell Fate ◽  
Cellular Stress ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Caspase Family ◽  
Mediate Cell

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

scholarly journals A Maternal Smad Protein Regulates Early Embryonic Apoptosis in Xenopus laevis

2002 ◽  
Vol 22 (5) ◽  
pp. 1317-1328 ◽  
Author(s):  
Yuko Miyanaga ◽  
Ingrid Torregroza ◽  
Todd Evans
Keyword(s):  
Functional Analysis ◽  
Cell Survival ◽  
Caspase 3 ◽  
Embryonic Cell ◽  
Early Embryogenesis ◽  
Cell Cycles ◽  
Smad Proteins ◽  
Smad Protein ◽  
Smad Signaling Pathway ◽  
A Cell

ABSTRACT We identified cDNAs encoding the Xenopus Smad proteins most closely related to mammalian Smad8, and we present a functional analysis of this activity (also referred to recently as xSmad11). Misexpression experiments indicate that xSmad8(11) regulates pathways distinct from those regulated by the closely related xSmad1. Embryos that develop from eggs depleted of xSmad8(11) mRNA fail to gastrulate; instead, at the time of gastrulation, they initiate a widespread program of apoptosis, via a CPP32/caspase 3 pathway. Embryos that avoid this fate display gastrulation defects. Activation of apoptosis is rescued by expression of xSmad8(11) but not xSmad1. Our results demonstrate an embryonic requirement for Smad8(11) activity and show that a maternally derived Smad signaling pathway is required for gastrulation and for mediating a cell survival program during early embryogenesis. We suggest that xSmad8(11) functions as part of a maternally derived mechanism shown previously by others to monitor Xenopus early embryonic cell cycles.

Intersex-like (IXL) Is a Cell Survival Regulator in Pancreatic Cancer with 19q13 Amplification

2007 ◽  
Vol 67 (5) ◽  
pp. 1943-1949 ◽  
Author(s):  
Riina Kuuselo ◽  
Kimmo Savinainen ◽  
David O. Azorsa ◽  
Gargi D. Basu ◽  
Ritva Karhu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Survival ◽  
A Cell

scholarly journals Mechanics defines the spatial pattern of compensatory proliferation

2021 ◽  
Author(s):  
Takumi Kawaue ◽  
Ivan Yow ◽  
Anh Phuong Le ◽  
Yuting Lou ◽  
Mavis Loberas ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Cell Loss ◽  
Spatial Inhomogeneity ◽  
Cellular Functions ◽  
Cell Numbers ◽  
Compensatory Proliferation ◽  
A Cell ◽  
Growth Promoting ◽  
Open Question

The number of cells in tissues is tightly controlled by cell division and cell death, and misregulation of cell numbers could lead to pathological conditions such as cancer. To maintain cell numbers in a tissue, a cell elimination process named programmed cell death or apoptosis, stimulates the proliferation of neighboring cells. This mechanism is called apoptosis-induced compensatory proliferation, which was originally reported more than 40 years ago. While only a limited number of the neigboring cells need to divide to compensate for apoptotic cell loss, the mechanisms that select cells for undergoing division remain an open question. Here we found that the spatial inhomogeneity in mechanotransduction through a growth-promoting transcription co-activator Yes-associated protein (YAP) in the neighboring tissue, accounts for the inhomogeneity of compensatory proliferation. Such inhomogeneous mechanotransduction arises from the combination of the non-uniform distribution of nuclear size, which is inherent in tissues, and the non-uniform pattern of mechanical force applied to the neighboring cells upon apoptosis. Our findings from a mechanical perspective complement the current biochemical understanding of compensatory growth and provide additional insights into cellular functions of how tissue precisely maintains its homeostasis.

scholarly journals 2219

2017 ◽  
Vol 1 (S1) ◽  
pp. 59-59
Author(s):  
Shaheen Kurani ◽  
Nicolas Madigan ◽  
Karl Clark ◽  
Stephen Ekker ◽  
Nathan Staff ◽  
...  
Keyword(s):  
Cell Survival ◽  
Targeted Delivery ◽  
Transfection Efficiency ◽  
Current Treatment ◽  
Safe Harbor ◽  
Systemic Delivery ◽  
Transcription Activator ◽  
Field Methods ◽  
A Cell ◽  
The Central Nervous System

OBJECTIVES/SPECIFIC AIMS: The current treatment for amyotrophic lateral sclerosis (ALS) includes systemic delivery of neurotrophic factors (NTFs). Although this approach may seem theoretically sound, NTF efficacy within the central nervous system (CNS) is largely limited by the blood-brain barrier. Thus, a cell-based approach, which allows for targeted delivery of molecular therapies locally from the CNS, could lead to a paradigm shift in the field. METHODS/STUDY POPULATION: The Windebank and Staff group at Mayo Clinic completed a Phase I dose-escalation safety trial of autologous, adipose-derived mesenchymal stem cells (adMSCs) in an effort to move toward personalized medical treatment of ALS. The adMSCs were injected into the intrathecal space by lumbar puncture in 27 patients and the results showed an excellent safety profile across a range of doses. The team is moving forward with this idea by using gene-editing technology to develop clinical-grade, genetically modified autologous MSCs. The patient-derived adMSCs are modified at defined “safe-harbor” regions of the human genome through transcription activator-like effector nuclease (TALEN) technology. RESULTS/ANTICIPATED RESULTS: Our results show that electroporating adMSCs with plasmid DNA leads to efficient GFP or TALEN transgene expression, but yields low cell survival and a low rate of genetic modification. DISCUSSION/SIGNIFICANCE OF IMPACT: It can be concluded that: (1) TALEN technology may be used to target safe harbor loci for gene integration to produce therapeutic adMSC for ALS. (2) Primary barriers to adMSC modification are inefficient TALEN and donor template uptake, low cutting efficiency, and poor cell survival after electroporation. Future directions include optimizing the protocol to obtain 48 base pairs in the homology arms and increasing transfection efficiency.

scholarly journals Identification of Proteins Associating with Glycosylphosphatidylinositol- Anchored T-Cadherin on the Surface of Vascular Endothelial Cells: Role for Grp78/BiP in T-Cadherin-Dependent Cell Survival

2008 ◽  
Vol 28 (12) ◽  
pp. 4004-4017 ◽  
Author(s):  
Maria Philippova ◽  
Danila Ivanov ◽  
Manjunath B. Joshi ◽  
Emmanouil Kyriakakis ◽  
Katharina Rupp ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Cell Survival ◽  
High Performance ◽  
Vascular Endothelial Cells ◽  
Surface Lipid ◽  
Gaba A ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Surface Signaling

ABSTRACT There is scant knowledge regarding how cell surface lipid-anchored T-cadherin (T-cad) transmits signals through the plasma membrane to its intracellular targets. This study aimed to identify membrane proteins colocalizing with atypical glycosylphosphatidylinositol (GPI)-anchored T-cad on the surface of endothelial cells and to evaluate their role as signaling adaptors for T-cad. Application of coimmunoprecipitation from endothelial cells expressing c-myc-tagged T-cad and high-performance liquid chromatography revealed putative association of T-cad with the following proteins: glucose-related protein GRP78, GABA-A receptor α1 subunit, integrin β3, and two hypothetical proteins, LOC124245 and FLJ32070. Association of Grp78 and integrin β3 with T-cad on the cell surface was confirmed by surface biotinylation and reciprocal immunoprecipitation and by confocal microscopy. Use of anti-Grp78 blocking antibodies, Grp78 small interfering RNA, and coexpression of constitutively active Akt demonstrated an essential role for surface Grp78 in T-cad-dependent survival signal transduction via Akt in endothelial cells. The findings herein are relevant in the context of both the identification of transmembrane signaling partners for GPI-anchored T-cad as well as the demonstration of a novel mechanism whereby Grp78 can influence endothelial cell survival as a cell surface signaling receptor rather than an intracellular chaperone.

scholarly journals Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms

Blood ◽  
1991 ◽  
Vol 78 (4) ◽  
pp. 1062-1068 ◽  
Author(s):  
M Zutter ◽  
D Hockenbery ◽  
GA Silverman ◽  
SJ Korsmeyer
Keyword(s):  
Cell Survival ◽  
Large Cell ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Protein Levels ◽  
Stage Of Development ◽  
T Cell Lymphomas ◽  
A Cell ◽  
Reactive Hyperplasia

Abstract The Bcl-2 proto-oncogene was discovered at the t(14;18) breakpoint found in most follicular B-cell lymphomas and some diffuse large-cell lymphomas. Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and extending cell survival by blocking programmed cell death. We examined Bcl-2 protein expression in 82 hematologic malignancies and reactive lymphoid processes. All lymphomas with Bcl-2 rearrangement demonstrated high levels of Bcl-2 protein. However, most follicular and diffuse lymphomas without Bcl-2 rearrangement also displayed intense Bcl-2 staining. In these cases, mechanisms other than classic translocation may be deregulation Bcl-2. The pattern of Bcl-2 staining in follicular lymphoma is the inverse of the pattern in reactive hyperplasia, confirming a role for Bcl-2 immunolocalization in routine diagnosis. Small lymphocytic malignancies, including small lymphocytic lymphoma, mantle zone lymphoma, and chronic lymphocytic leukemia, expressed intermediate levels of Bcl-2. Bcl-2 protein varied in plasma cell dyscrasias. Bcl-2 protein levels in T-cell lymphomas reflected their corresponding stage of development. No substantial Bcl- 2 was present in the Reed-Sternberg cells of nodular sclerosing Hodgkin's disease. Chronic myelogenous leukemia was strongly positive for Bcl-2, consistent with the presence of Bcl-2 in normal myeloid progenitors. Immunohistochemistry identified an expanded spectrum of hematopoietic neoplasms in which Bcl-2 may provide a cell survival advantage.

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