hnRNP-K and Purα act together to repress the transcriptional activity of the CD43 gene promoter

Abstract

CD43 is an abundant, heavily glycosylated molecule expressed specifically on the surface of leukocytes and platelets. When leukocytes are at rest, CD43 acts to prevent both homotypic and heterotypic interactions. However, during leukocyte activation CD43 expression is repressed, facilitating the intercellular contact required for chemotaxis, phagocytosis, aggregation, adhesion to endothelium, and transendothelial migration. Consequently, CD43 repression plays a vital role both in innate and acquired immunity. Here we report that a dramatic down-regulation of CD43 mRNA levels occurs during activation of the leukocytic cell line K562. This repression coincides with repression of the transcriptional activity of the CD43 gene promoter. We have determined that heterogeneous nuclear ribonucleopro- IntroductionCD43 is a heavily glycosylated transmembrane molecule that plays a critical role in leukocyte activation and adhesion. [1][2][3] The importance of CD43 is demonstrated by 2 immunodeficiency diseases, Wiskott-Aldrich syndrome (WAS) and the early stages of HIV infection. [4][5][6][7][8][9] The etiology of both diseases involves the development of defects in CD43. Patients with WAS, which is an X chromosome-linked, recessive disorder, express defective CD43 on the surface of their T lymphocytes. Affected males are subject to recurring opportunistic infections and do not respond to carbohydrate antigens, reflecting defects in T lymphocyte function. In addition, patients suffer from eczema and thrombocytopenia with platelets of reduced size and function. With regard to HIV infection, the finding that all affected individuals have circulating anti-CD43 antibodies has led to the suggestion that these autoantibodies contribute to severe immunodeficiency. 8 CD43 is composed of 381 amino acids divided between a 235-residue extracellular region, a 23-residue transmembrane region, and a 123-amino acid C-terminal intracellular region. 10,11 The extracellular region contains approximately 84 sialylated O-linked carbohydrate units and appears by electron microscopy to be a rodlike structure extending 45 nm from the cell surface. 12 Comparison of the rat, mouse, and human sequences indicates that the intracellular domain has been highly conserved during evolution, suggesting a critical function. The intracellular domain anchors CD43 to the cytoskeleton by binding actin, ezrin, and moesin. 13,14 When leukocytes are at rest, CD43 maintains their circulation within the bloodstream by preventing intercellular adhesion. This function is achieved by virtue of the size and strong negative charge of the extracellular domain. [15][16][17][18] During leukocyte activation, CD43 expression is dramatically down-regulated, allowing intercellular interactions mediated by molecules such as the ␤ 2 integrins. Intercellular interactions are also actively facilitated by CD43, which, due to changes in glycosylation, switches from being an antiadhesion to a proadhesion molecule. [19][20][21][22][23][24][25][26][27][28] The proadhesive function of C...

Differential protein synthesis and expression levels in normal and neoplastic human prostate cells and their regulation by type I and II interferons

“…hnRNP-K's multiple binding partners include members of the Src family of proto-oncogenes and transcription regulators such as TATA binding protein (TBP) and various zinc-finger-containing transcriptional repressors (Bomsztyk et al, 1997). hnRNP-K can act both as an activator and a repressor of transcription and as a translational repressor involved in regulated mRNA silencing (Ostareck et al, 1997;Da Silva et al, 2002;Ostareck-Lederer et al, 2002). hnRNP-K activates transcription of the c-myc gene following binding to the specific CT element of its promoter (Nakielny and Dreyfuss, 1999).…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…When leukocytes are activated, there is a downregulation of CD43 and CD45 along with a reduction in their sialylation and a concomitant up-regulation of the proadhesive β2-integrin family. [358][359][360][361][362][363] The induction of this reciprocal expression of anti-adhesion and pro-adhesion forces results in leukocytes acquiring an adhesive phenotype capable of extravasation and infiltration into organs such as the kidney (figure 2).…”

“…261,262 Under normoxic conditions Purα has been shown to repress transcription of the CD43 gene. 361,362 Consequently, this transcription factor appears to act as a master regulator, coordinating the reciprocal expression of anti-adhesion and pro-adhesion molecules to drive leukocyte adhesion. While hypoxia utilizes Purα to induce β2-integrin expression, it remains to be determined whether hypoxia represses expression of either CD43 or CD45, and if it does, whether Purα is involved.…”

The Transcriptional Activator Pti4 Is Required for the Recruitment of a Repressosome Nucleated by Repressor SEBF at the PotatoPR-10aGene

“…In an exemplary case, hnRNP C1/C2 purified from an in vivo source with its associated cofactors could bind the doublestranded DNA version of its cognate sequence, while the recombinant version, devoid of cofactors, could not (Mahajan et al, 2005). The same rationale could be applied to SEBF, where Pti4 may stimulate a latent helicase activity in SEBF or help recruit such an activity to the repressosome, as is the case in the hnRNP K-Pura repressosome (Da Silva et al, 2002). Although it is unclear at present which mechanism governs the Pti4-assisted recruitment of SEBF to PR-10a, these proposed scenarios constitute future areas of potential exploration.…”