The mammalian SWI/SNF chromatin remodeling complexes play essential roles in cell cycle control through the transcriptional regulation of cell-cycle-specific genes. These complexes depend on the energy of ATP hydrolysis provided by the BRG1 or BRM catalytic subunit. They contain seven or more noncatalytic subunits, some being constitutive components, with others having paralogs that assemble in a combinatory manner producing different SWI/SNF-related complexes with specific functions. ARID1A and ARID1B are mutually exclusive subunits of the BAF complex. The specific presence of these subunits in the complex has been demonstrated to determine whether SWI/SNF functions as a corepressor (ARID1A) or as a coactivator (ARID1B) of the cell cycle genes. Our aim has been to analyze the relevance of the ARID1 subunits in development. We have compared the patterns of expression of these two genes through various mouse embryonic stages. Arid1a is expressed widely and intensively, whereas Arid1b is poorly transcribed and expressed in selected regions. Moreover, ARID1A and ARID1B present different kinetics of expression in the cell cycle. ARID1A accumulates in G0 and is downregulated throughout the cell cycle phases but is completely eliminated during mitosis, whereas ARID1B is expressed at comparable levels at all phases, even during mitosis. These kinetics probably affect the incorporation patterns of the ARID1 proteins to the complex and hence modulate SWI/SNF activity during proliferation and arrest.

SummaryCD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both Y 105 of PKM2 and of Y 705 of signal transducer and activator of transcription 3 was induced in response to TCR+CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-jB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes.

Mycobacterium tuberculosis is the causal agent of tuberculosis. Tumor necrosis factor alpha (TNF-␣), transforming growth factor ␤ (TGF-␤), and gamma interferon (IFN-␥) secreted by activated macrophages and lymphocytes are considered essential to contain Mycobacterium tuberculosis infection. The CD43 sialomucin has been reported to act as a receptor for bacilli through its interaction with the chaperonin Cpn60.2, facilitating mycobacterium-macrophage contact. We report here that Cpn60.2 induces both human THP-1 cells and mouse-derived bone marrow-derived macrophages (BMMs) to produce TNF-␣ and that this production is CD43 dependent. In addition, we present evidence that the signaling pathway leading to TNF-␣ production upon interaction with Cpn60.2 requires active Src family kinases, phospholipase C-␥ (PLC-␥), phosphatidylinositol 3-kinase (PI3K), p38, and Jun N-terminal protein kinase (JNK), both in BMMs and in THP-1 cells. Our data highlight the role of CD43 and Cpn60.2 in TNF-␣ production and underscore an important role for CD43 in the host-mycobacterium interaction.

Aberrant expression of CD43 in malignant tumors of nonhematopoietic origin such as those from lung, cervix, colon, and breast has been shown to correlate with poor prognosis, providing tumor cells with enhanced motility, anchorage-independent growth, and in vivo tumor size, while protecting the cells of NK lysis and apoptosis. To further characterize the role of CD43 in cell transformation, we tested whether interfering its expression modified the capacity of the A549 non-small cell lung cancer cells to secrete molecules contributing to malignancy. The proteomic analysis of the secretome of serumstarved A549 cells revealed that cells expressing normal levels of CD43 released significantly high levels of molecules involved in extracellular matrix organization, angiogenesis, platelet degranulation, collagen degradation, and inflammation, as compared to CD43 RNAi cells. This data reveals a novel and unexpected role for CD43 in lung cancer development, mainly in remodeling the tumor microenvironment.