TRA
cell receptor alpha chain MC.7.G5 precursor (MC.7.G5 TRA) (TR alpha chain TRAV38-2DV8*01J31*01C*01)
Publications[править]
Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive ( ) cells converted to a [[TRA]]-1-60 ( ) intermediate state. These early ESRG ( ) or [[TRA]]-1-60 ( ) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC.
MeSH Terms
- Antigens, Surface
- Cell Line
- Cell Proliferation
- Cellular Reprogramming
- Cyclin-Dependent Kinase Inhibitor p16
- Humans
- Induced Pluripotent Stem Cells
- Phosphorylation
- Proteoglycans
- Proto-Oncogene Proteins c-myc
- RNA Interference
- RNA, Small Interfering
- Retinoblastoma Protein
- Transcription Factors
- Tripartite Motif Proteins
- Ubiquitin-Protein Ligases
Keywords
- LIN41
- MYC
- immortalization
- induced pluripotent stem cell
- pluripotency
- post-transcriptional regulation
- proliferation
- reprogramming
- senescence
A fascinating aspect of sexual dimorphism in various animal species is that the two sexes differ substantially in lifespan. In humans, for example, women's life expectancy exceeds that of men by 3-7 years. Whether this trait can be attributed to dissimilar lifestyles or genetic (regulatory) factors remains to be elucidated. Herein, we demonstrate that in the nematode Caenorhabditis elegans, the significantly longer lifespan of hermaphrodites-which are essentially females capable of sperm production-over males is established by [[TRA]]-1, the terminal effector of the sex-determination pathway. This transcription factor directly controls the expression of daf-16/FOXO, which functions as a major target of insulin/IGF-1 signaling (IIS) and key modulator of aging across diverse animal phyla. [[TRA]]-1 extends hermaphrodite lifespan through promoting daf-16 activity. Furthermore, [[TRA]]-1 also influences reproductive growth in a DAF-16-dependent manner. Thus, the sex-determination machinery is an important regulator of IIS in this organism. These findings provide a mechanistic insight into how longevity and development are specified unequally in the two genders. As [[TRA]]-1 is orthologous to mammalian GLI (glioma-associated) proteins, a similar sex-specific mechanism may also operate in humans to determine lifespan.
MeSH Terms
- Aging
- Animals
- Caenorhabditis elegans
- Female
- Male
- Sex Determination Processes
- Sex Factors
Keywords
Caenorhabditis elegans
daf-16/FOXO
- TRA-1/GLI
- aging
- dauer development
- insulin/IGF-1 signaling
- sex determination
Although autoimmune disorders are a significant source of morbidity and mortality in older individuals, the mechanisms governing age-associated increases in susceptibility remain incompletely understood. Central T cell tolerance is mediated through presentation of self-antigens by cells constituting the thymic microenvironment, including epithelial cells, dendritic cells, and B cells. Medullary thymic epithelial cells (mTECs) and B cells express distinct cohorts of self-antigens, including tissue-restricted self-antigens ([[TRA]]s), such that developing T cells are tolerized to antigens from peripheral tissues. We find that expression of the [[TRA]] transcriptional regulator Aire, as well as Aire-dependent genes, declines with age in thymic B cells in mice and humans and that cell-intrinsic and cell-extrinsic mechanisms contribute to the diminished capacity of peripheral B cells to express Aire within the thymus. Our findings indicate that aging may diminish the ability of thymic B cells to tolerize T cells, revealing a potential mechanistic link between aging and autoimmunity.
MeSH Terms
- Adult
- Aging
- Animals
- Autoantigens
- B-Lymphocytes
- Central Tolerance
- Child, Preschool
- Humans
- Infant
- Mice
- Middle Aged
- Thymus Gland
- Transcription Factors
Keywords
- Aire
- B cell
- aging
- thymus
Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with either sporadic or genetic origins characterized by the progressive degeneration of motor neurons. At the cellular level, ALS neurons show protein misfolding and aggregation phenotypes. Transactive response DNA-binding protein 43 (TDP-43) has recently been shown to be associated with ALS, but the early pathophysiological deficits causing impairment in motor function are unknown. Here we used Caenorhabditis elegans expressing mutant TDP-43(A315T) in motor neurons and explored the potential influences of calcium (Ca(2 )). Using chemical and genetic approaches to manipulate the release of endoplasmic reticulum (ER) Ca(2 )stores, we observed that the reduction of intracellular Ca(2 ) ([Ca(2 )]i) rescued age-dependent paralysis and prevented the neurodegeneration of GABAergic motor neurons. Our data implicate elevated [Ca(2 )]i as a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca(2 )-regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43(A315T)-associated neuronal toxicity. This work both underscores the potential of the C. elegans system to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca(2 ) release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance.
MeSH Terms
- Aging
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Calcium
- Calcium Signaling
- Calpain
- Caspases
- DNA-Binding Proteins
- Endoplasmic Reticulum
- GABAergic Neurons
- Locomotion
- Motor Neurons
- Necrosis
- Paralysis
- Protease Inhibitors
Keywords
- ALS
- C. elegans
- ER
- TDP-43
- calcium
- necrosis