Biomedical subjects

Lisa Hendry

Publications and source records attributed to Lisa Hendry.

3 recordsLinked to original sources

PubMed2006

Lack of suppressive CD4+CD25+FOXP3+ T cells in advanced stages of primary cutaneous T-cell lymphoma.

Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common primary cutaneous T-cell lymphomas (CTCLs). In an ex vivo study, we investigated the percentage, phenotype, and suppressive function of CD4+CD25+ regulatory T cells (Tregs) from peripheral blood of CTCL patients. The percentage of Tregs did not differ significantly between patients and controls. Functional assays demonstrated a dichotomy in Treg function: in four out of 10 patients CD4+CD25+ T cells were incapable of suppressing autologous CD4+CD25- T-cell proliferation, whereas suppressive function was intact in the other six patients. Suppressive activity of Tregs inversely correlated with the peripheral blood tumor burden. T-plastin gene expression, used as a Sezary cell marker, confirmed that Sezary cells were heterogeneous for CD25 expression. Mixed lymphocyte reactions demonstrated that CD4+CD25- T cells from patients who lacked functional Tregs were susceptible to suppression by Tregs from healthy controls, and had not become suppressive themselves. Furthermore, we found reduced expression of Foxp3 in the CD4+CD25+ Tregs of these patients relative to the other six CTCL patients and controls. Our findings thus indicate a dysfunction of peripheral Tregs in certain CTCL patients, which correlates with tumor burden.

Aged↗

PubMed2004

A single residue modulates tyrosine dephosphorylation, oligomerization, and nuclear accumulation of stat transcription factors.

The NH(2) terminus of Stat proteins forms a versatile protein interaction domain that is believed to use discrete surfaces to mediate oligomerization and tyrosine dephosphorylation of Stat dimers. Here we show for Stat1 and Stat5a/b that these interfaces overlap and need to be reassigned to an unrelated region of the N-domain. Unexpectedly, our study showed for Stat1 that defective oligomerization of DNA-bound dimers was associated with prolonged interferon-induced nuclear accumulation. This uncoupling of DNA binding and nuclear retention was explained by the concomitant dephosphorylation deficiency that both Stat1 and Stat5a/b have in common and that for Stat1 was due to defective dephosphorylation by the phosphatase TC45. Furthermore, diminished N-domain-mediated oligomerization affected transcriptional activation by both Stat1 and Stat5a/b in a promoter-specific manner. DNA binding analysis indicated that oligomerization of Stats on DNA may be common, irrespective of the presence of multiple canonical binding sites. Accordingly, also transcription from promoters with only a single discernable gamma-activated sequence site was negatively effected by reduced tetramerization. Thus, these results indicate that defective oligomerization cannot generally be compensated for by enhanced tyrosine phosphorylation and prolonged nuclear accumulation. In addition, these data clarify the role of DNA binding in nuclear retention of Stat1.

Cell Nucleus↗

PubMed2004

Regulation of STAT signalling by proteolytic processing.

Interaction of cytokines with their cognate receptors leads to the activation of latent transcription factors, the signal transducer and activator of transcription (STAT) proteins. Numerous studies have identified the critical roles played by STAT proteins in regulating cell proliferation, differentiation and survival. Consequently, the activity of STAT proteins is negatively regulated by a variety of different mechanisms, which include alternative splicing, covalent modifications, protein-protein interactions with negative regulatory proteins and proteolytic processing by proteases. Cleavage of STAT proteins by proteases results in the generation of C-terminally truncated proteins, called STATgamma, which lack the transactivation domain and behave as functional dominant-negative proteins. Currently, STATgamma isoforms have been identified for Stat3, Stat5a, Stat5b and Stat6 in different cellular contexts and biological processes. Evidence is mounting for the role of as yet unidentified serine proteases in the proteolytic processing of STAT proteins, although at least one cysteine protease, calpain is also known to cleave these STATs in platelets and mast cells. Recently, studies of acute myeloid leukaemia and cutaneous T cell lymphoma patients have revealed important roles for the aberrant expression of Stat3gamma and Stat5gamma proteins in the pathology of these diseases. Together, these findings indicate that proteolytic processing is an important mechanism in the regulation of STAT protein biological activity and provides a fertile area for future studies.

Disease↗