Biomedical subjects

Alessandra Vacca

Publications and source records attributed to Alessandra Vacca.

5 recordsLinked to original sources

PubMed2006

Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia.

Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. 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. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-kappaB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-kappaB via IKKbeta/IKKalpha/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-alpha genes. In contrast, upon pTalpha deletion, Notch3 binds IKKalpha and maintains NF-kappaB activation through an alternative pathway, depending on an NIK-independent IKKalpha homodimer activity. The consequent NF-kappaB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-alpha genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-kappaB activity, leading to differential NF-kappaB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.

Animals↗

PubMed2005

Cross talk among Notch3, pre-TCR, and Tal1 in T-cell development and leukemogenesis.

Integrated pathways are believed to determine hematopoietic cell fate and/or neoplastic transformation. Notch signaling has been shown to regulate T-cell differentiation and leukemogenesis. However, specific target genes and molecular partners are not fully elucidated. We show that Notch3 activation sustains aberrant SCL/Tal1 overexpression and phosphorylation in mature thymocytes. Furthermore, we define the role of SCL/Tal1 as a component of an activator complex, including phosphorylated Tal1 and Sp1, that specifically enhances cyclin D1 expression and demonstrate that Tal1/Sp1 specifically co-occupy the D1 promoter in vivo, only in the presence of pre-T-cell receptor (TCR). We therefore conclude not only that cyclin D1 is a target of the Tal1/Sp1 complex, but also that Notch3-dependent activation of pre-TCR/ERK signaling regulates SCL/Tal1 function.

Animals↗

PubMed2005

PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia.

Protein kinase (PK)C theta is a critical regulator of mature T-cell activation and proliferation, being implicated in TCR-triggered nuclear factor (NF)-kappa B activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pT alpha/pre-TCR and constitutive activation of NF-kappa B characterize the T-cell leukemia/lymphoma developing in Notch3-IC transgenic mice. We report here that PKC theta is a downstream target of Notch3 signaling and that its activation and membrane translocation require a functional pre-TCR in order to trigger NF-kappa B activation in thymocytes and lymphoma cells of transgenic mice. Furthermore, deletion of PKC theta in Notch3-IC transgenic mice reduces the incidence of leukemia, correlating with decreased NF-kappa B activation. This paper therefore suggests that PKC theta mediates the activation of NF-kappa B by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.

Animals↗

PubMed2003

Two distinctive HLA haplotypes harbor the B27 alleles negatively or positively associated with ankylosing spondylitis in Sardinia: implications for disease pathogenesis.

OBJECTIVE: To compare haplotype distribution in HLA-B27-positive patients with ankylosing spondylitis (AS) and healthy control subjects possessing either AS-associated HLA-B27 alleles or the non-AS-associated HLA-B*2709 allele. METHODS: DNA samples from 47 HLA-B27-positive patients with AS and 76 HLA-B27-positive healthy controls (19 positive and 57 negative for B*2709) living in different areas of Sardinia were collected and typed for HLA class I and class II alleles. The third exon of the B27 gene was analyzed for the presence of Asp(116) or His(116), which differentiates B*2709 from the other two B27 subtypes (B*2705 and B*2702) that are mostly found in Sardinia. The parents of 6 subjects positive for B*2709 were also typed for HLA class I and class II alleles. Statistical analysis was performed by Fisher's exact test. RESULTS: In Sardinia, the B27 alleles conferring susceptibility to AS appear to be more frequently carried by a haplotype (A2;B27;Cw2;DR16) that reaches its highest frequency in patients with AS (A2 80.8%, B27 100%, Cw2 83%, and DR16 74.5%). Conversely, the non-AS-associated B*2709 allele is more frequently found together with other HLA alleles whose frequencies are inversely correlated with the disease (A32 or A30, Cw1, and DR12). Familial analysis of 6 subjects positive for HLA-B*2709 confirmed the existence of a "Sardinian" haplotype that is not associated with AS (A32;B*2709;Cw1;DR12). CONCLUSION: In Sardinia, 2 distinct haplotypes harbor the non-AS-associated HLA-B*2709 allele or the AS-associated B27 alleles. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 may play some role in conferring susceptibility to AS.

Adult↗

PubMed2003

Notch3, another Notch in T cell development.

Different members of the Notch family have been described to play a critical role in T cell lineage commitment and T cell development and functions. Nevertheless, whether they act as redundant molecules, by affecting the same molecular mechanisms, or play distinct roles in T cell differentiation and/or functions is not clear. Altered Notch3 signaling impairs the developmentally regulated interplay between pre-TCR and NF-kappaB signaling and allows the disruption of early thymocyte differentiation and the development of T cell leukemia, thus identifying the crucial role of Notch3 receptor in the coordination of T cell differentiation and growth control.

Animals↗