Biomedical subjects

Isabelle Alberti

Publications and source records attributed to Isabelle Alberti.

3 recordsLinked to original sources

PubMed2003

Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases.

Forkhead family transcription factors are critical regulators of cell cycle progression and apoptosis in hematopoietic cells. Here, we show that FOXO3a (also known as FKHRL1) is a new substrate of caspase-3-like proteases during apoptosis in T lymphocytes. FOXO3a was cleaved in vivo by caspases in leukemic Jurkat cells following engagement of Fas (CD95) receptor, staurosporine, and etoposide treatment, but not following engagement of CD99, a caspase-independent cell death inducer. Caspase-mediated cleavage of FOXO3a was also observed in CD4+ peripheral T cells subjected to activation-induced cell death. The expression of the death adapter FADD and caspase-8 was required for Fas-induced FOXO3a cleavage, but activation of survival pathways by overexpression of FLICE-inhibitory protein or phorbol myristate acetate treatment prevented it. FOXO3a was cleaved in vitro by caspase-3-like proteases at the consensus sequence DELD304A, releasing the N-terminal DNA-binding domain of FOXO3a from its C-terminal transactivating domain. Whereas full-length FOXO3a enhanced Forkhead response element-dependent transcription and apoptosis in Jurkat cells, both fragments were inactive to promote gene activation and cell death. In contrast, a caspase-resistant FOXO3a mutant exhibited enhanced transcriptional and proapoptotic activities. Together, these results indicate that the proteolytic cleavage of FOXO3a by caspases may represent a novel regulatory mechanism of FOXO3a activity during death receptors signaling.

Adaptor Proteins, Signal Transducing↗

PubMed2002

CD99 isoforms expression dictates T cell functional outcomes.

CD99, a unique integral membrane protein present on the surface of all human T cells, has previously been shown to regulate cell function and fate. In peripheral T cells, it triggers immediate activation of alpha4b1 integrin and cell arrest on inflamed vascular endothelium, whereas it mediates an apoptotic signal in double-positive thymocytes undergoing the selection process. Two isoforms of CD99 exist, a long form corresponding to the full-length protein and a short form harboring a deletion in the intracytoplasmic segment. Here, we show that while peripheral T cells display exclusive expression of the long form, double-positive thymocytes express both isoforms. Moreover, differential expression of these two CD99 molecules can lead to distinct functional outcomes. Expression of the long form in a CD99-deficient Jurkat T cell line is sufficient to promote CD99-induced cell adhesion, whereas coexpression of the two isoforms is required to trigger T-cell death. When coexpressed, the two proteins form covalent heterodimers, which locate within glycosphingolipidic rafts and induce sphingomyelin degradation. Cholesterol depletion experiments show that this localization is required for the induction of apoptosis. Thus, the surface expression pattern of CD99 isoforms determines T-cell functional outcomes.

12E7 Antigen↗

PubMed2002

The two-signal model of T-cell activation after 30 years.

The two-signal model of T-cell activation is still valid after 30 years. The recent understanding of the first signal intricacy and its tight relationship with the second signal have thrown decisive light on T-cell activation processes and the complex molecular events that occur on the surface and within the T cell. Furthermore, the recognition of numerous accessory pathways that, in addition to the CD28 and CD40 pathways, operate to manage antigen-presenting cell T cell cooperation in view of lymphocyte activation, disclose the exquisite and numerous regulatory events that compose the second signal.

Animals↗