Disease relevance of Ptcra

• Notch3-transgenic premalignant thymocytes and T lymphoma cells overexpress pTalpha/pre-TCR and display constitutive activation of NF-kappaB, providing survival signals for immature thymocytes [2].

High impact information on Ptcra

• The pre-T cell receptor (pre-TCR) that minimally consists of the TCR beta chain and the disulfide-linked pre-T cell receptor alpha (pT alpha) chain in association with signal-transducing CD3 molecules rescues from programmed cell death cells with productive TCR beta rearrangements [3].
• Experiments in pT alpha gene-deficient mice show that the pre-TCR has a crucial role in maturation as well as allelic exclusion of alpha beta T cells but is not required for the development of gamma delta-expressing cells [3].
• The newly discovered pT alpha gene encodes a transmembrane protein that belongs to the Ig superfamily and contains a cytoplasmic tail that, however, has no essential function in signal transduction, which is mediated by CD3 molecules and most likely p56lck [3].
• Unlike the lambda 5 pre-B cell receptor protein, the pT alpha chain is a type I transmembrane protein whose cytoplasmic tail contains two potential phosphorylation sites and a Src homology 3 (SH3)-domain binding sequence [4].
• Thus, the function of the endogenous TCRgamma/pTalpha is limited by the transcriptional down-regulation of TCRgamma genes that normally accompanies DP cell development [5].

Biological context of Ptcra

• Restoration of thymopoiesis in pT alpha-/- mice by anti-CD3epsilon antibody treatment or with transgenes encoding activated Lck or tailless pT alpha [6].
• Tracing lymphopoiesis with the aid of a pTalpha-controlled reporter gene [7].
• The human pTalpha gene is expressed in immature but not mature T cells and is located at the p21.2-p12 region of the short arm of chromosome 6 [8].
• Amino acid sequence comparison of human pTalpha with the mouse pTalpha molecule reveals high sequence homology in the extracellular as well as the transmembrane region [8].
• The human pTalpha gene, like the murine pTalpha gene, consists of four exons. Conserved splice sites allow an alternative splicing which produces a shorter pTalpha isoform, which lacks the Ig-like domain [1].
• Reverse transcriptase-polymerase chain reaction (RT-PCR) and DNA-PCR analyses showed that some of the primary colony cells are differentiated sufficiently to express messenger RNA (mRNA) of T-cell receptor (TCR) beta-chain and pre-TCR alpha (pTalpha) and, although not frequently, to perform Dbeta-Jbeta rearrangement of the TCR gene [9].

Anatomical context of Ptcra

• With help of a hCD25 reporter controlled by pre-T cell receptor alpha (Ptcra) regulatory elements, T cell precursors were identified in peripheral blood [10].
• Thymocytes representing all stages of T-cell differentiation were detected in the thymus of pTalpha-/- chimeric mice, indicating that thymocyte development can occur without pTalpha [11].
• To examine the function of the transmembrane pTalpha chain during tbymocyte development, we generated pTalpha-/- embryonic stem cells and assayed their ability to differentiate into lymphoid cells in vivo after injection into recombination-activating gene (RAG)-2-deficient blastocysts [11].
• Expression of pTalpha mutants in transgenic mice, retrovirally transduced T cell precursors and cell lines showed that the pTalpha cytoplasmic tail, in particular the proline-rich domain, plays a crucial role in pre-TCR signaling and T cell development [12].
• However, we could not detect expression of pT alpha or of recombination-activating gene 1 in CD34+ cord blood cells [13].

Associations of Ptcra with chemical compounds

• The mouse pre-T-cell receptor alpha (pT alpha) chain is a 33,000 M(r) glycoprotein expressed on the surface of immature thymocytes as a disulfide-linked heterodimer with the T-cell receptor beta (TCR beta) chain, and in association with proteins of the CD3 complex [14].
• In contrast, the pTalpha juxtamembrane cysteine appeared to be dispensable for pre-TCR function [12].

Regulatory relationships of Ptcra

• It has been shown that Notch3-induced T-cell leukaemia is abrogated by the inactivation of pTalpha/pre-T-cell antigen receptor (pre-TCR) [15].

Other interactions of Ptcra

• The pre-T-cell receptor, composed of the T-cell receptor (TCR) beta chain (TCRbeta), pre-Talpha (pTalpha) chain, and CD3 molecules, has been postulated to be a transducer of signals during the early stages of T-cell development [11].
• We generated mice selectively lacking expression of CD3gamma, in which expression of CD3delta, CD3epsilon, CD3zeta, pTalpha and TCRbeta remained undisturbed [16].
• T lineage characteristics are acquired sequentially, with germ-line T cell antigen receptor-beta transcripts detected very early, followed by CD3epsilon and terminal deoxynucleotidyl transferase, then pTalpha, and finally RAG1 [17].
• Second, SDCs and TDCs from CD3epsilon(-/-) mice do not secrete IL-12 in vitro after different stimulations, whereas DCs from pTalpha(-/-) mice, possessing reduced T cell number, and RAG-2(-/-) mice, produce an IL-12 level similar to that of WT DCs [18].
• These changes include down-regulation of CD25, recombinase-activating gene (RAG)-1, RAG-2, and pTalpha; and the up-regulation of TCRalpha germline transcripts [19].

Analytical, diagnostic and therapeutic context of Ptcra

• Furthermore, electrophoretic mobility shift assays suggested that E47 binds directly to both the pT alpha promoter and enhancer in vitro [20].

References