Biomaterial Database

Negative regulation of TCR signaling by NF-kappaB2/p100. 2007

Diana Legarda-Addison, and Adrian T Ting

Immunology Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

The positive regulation of the NF-kappaB-signaling pathway in response to TCR stimulation has been well-studied. However, little is known about the negative regulation of this pathway in T cells. This negative regulation is crucial in controlling the duration of TCR signaling and preventing abnormal lymphocyte activation and proliferation. Therefore, understanding the negative regulation of TCR-mediated NF-kappaB signaling is essential in understanding the mechanisms involved in T cell function and homeostasis. TCR stimulation of human CD4+ T cells resulted in an increase in NF-kappaB2/p100 expression with no appreciable increase in p52, its cleavage product. Due to the presence of inhibitory ankyrin repeats in the unprocessed p100, this observation suggests that p100 may function as a negative regulator of the NF-kappaB pathway. Consistent with this hypothesis, ectopic expression of p100 inhibited TCR-mediated NF-kappaB activity and IL-2 production in Jurkat T cells. Conversely, knockdown of p100 expression enhanced NF-kappaB transcriptional activity and IL-2 production upon TCR activation. p100 inhibited the pathway by binding and sequestering Rel transcription factors in the cytoplasm without affecting the activity of the upstream IkappaB kinase. The kinetics and IkappaB kinase gamma/NF-kappaB essential modulator dependency of p100 induction suggest that NF-kappaB2/p100 acts as a late-acting negative-feedback signaling molecule in the TCR-mediated NF-kappaB pathway.

UI	MeSH Term	Description	Entries
D007376	Interleukin-2	A soluble substance elaborated by antigen- or mitogen-stimulated T-LYMPHOCYTES which induces DNA synthesis in naive lymphocytes.	IL-2,Lymphocyte Mitogenic Factor,T-Cell Growth Factor,TCGF,IL2,Interleukin II,Interleukine 2,RU 49637,RU-49637,Ro-23-6019,Ro-236019,T-Cell Stimulating Factor,Thymocyte Stimulating Factor,Interleukin 2,Mitogenic Factor, Lymphocyte,RU49637,Ro 23 6019,Ro 236019,Ro236019,T Cell Growth Factor,T Cell Stimulating Factor
D011948	Receptors, Antigen, T-Cell	Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (CD3 COMPLEX). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains.	Antigen Receptors, T-Cell,T-Cell Receptors,Receptors, T-Cell Antigen,T-Cell Antigen Receptor,T-Cell Receptor,Antigen Receptor, T-Cell,Antigen Receptors, T Cell,Receptor, T-Cell,Receptor, T-Cell Antigen,Receptors, T Cell Antigen,Receptors, T-Cell,T Cell Antigen Receptor,T Cell Receptor,T Cell Receptors,T-Cell Antigen Receptors
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013601	T-Lymphocytes	Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.	T Cell,T Lymphocyte,T-Cells,Thymus-Dependent Lymphocytes,Cell, T,Cells, T,Lymphocyte, T,Lymphocyte, Thymus-Dependent,Lymphocytes, T,Lymphocytes, Thymus-Dependent,T Cells,T Lymphocytes,T-Cell,T-Lymphocyte,Thymus Dependent Lymphocytes,Thymus-Dependent Lymphocyte
D014158	Transcription, Genetic	The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.	Genetic Transcription
D015398	Signal Transduction	The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.	Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015536	Down-Regulation	A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.	Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor
D016328	NF-kappa B	Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.	Immunoglobulin Enhancer-Binding Protein,NF-kappa B Complex,Nuclear Factor kappa B,Transcription Factor NF-kB,kappa B Enhancer Binding Protein,Ig-EBP-1,NF-kB,NF-kappaB,Nuclear Factor-Kappab,Complex, NF-kappa B,Enhancer-Binding Protein, Immunoglobulin,Factor NF-kB, Transcription,Factor-Kappab, Nuclear,Ig EBP 1,Immunoglobulin Enhancer Binding Protein,NF kB,NF kappa B Complex,NF kappaB,NF-kB, Transcription Factor,Nuclear Factor Kappab,Transcription Factor NF kB
D051550	I-kappa B Kinase	A protein serine-threonine kinase that catalyzes the PHOSPHORYLATION of I KAPPA B PROTEINS. This enzyme also activates the transcription factor NF-KAPPA B and is composed of alpha and beta catalytic subunits, which are protein kinases and gamma, a regulatory subunit.	CHUK Kinase,Conserved Helix-Loop-Helix Ubiquitous Kinase,I Kappa B alpha-Associated Protein Kinase,I kappa B Kinase,IKBKB,IKK 1 Kinase,IKK 2 Kinase,IKK alpha,IKK beta,IKK epsilon,IKK gamma,IKKepsilon,IkappaB Kinase,IkappaB Kinase alpha,IkappaB Kinase beta,IkappaB Kinase epsilon,IkappaB Kinase gamma,IkappaBalpha Kinase,NF-kappaB Essential Modifier,NK-kappa B-Activating Kinase NAK,B Kinase, I-kappa,Conserved Helix Loop Helix Ubiquitous Kinase,Essential Modifier, NF-kappaB,I Kappa B alpha Associated Protein Kinase,Kinase alpha, IkappaB,Kinase beta, IkappaB,Kinase epsilon, IkappaB,Kinase, I-kappa B,Kinase, IkappaB,NF kappaB Essential Modifier,NK kappa B Activating Kinase NAK
D052003	NF-kappa B p52 Subunit	A component of NF-kappa B transcription factor. It is proteolytically processed from NF-kappa B p100 precursor protein and is important for maturation of B-LYMPHOCYTES and adaptive HUMORAL IMMUNITY.	NF-kappa B p100 Precursor Protein,NF-kappaB p52,NF-kappaB p52 Subunit,NF-kappaB2,NF-kappaB2 p100,NFKB2 Transcription Factor,NK-kappa B p52,Transcription Factor H2TF1,H2TF1, Transcription Factor,NF kappa B p100 Precursor Protein,NF kappa B p52 Subunit,NF kappaB p52,NF kappaB p52 Subunit,NF kappaB2,NF kappaB2 p100,NK kappa B p52,Transcription Factor, NFKB2,p100, NF-kappaB2,p52, NK-kappa B