Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sezary Syndrome (SzS) is a leukemic variant of cutaneous T-cell lymphoma characterized by the accumulation of clonal neoplastic CD4+ T cells. The signal transducers and activators of transcription (STAT) family members, Stat5a and Stat5b, play an important role in regulating T-cell activation. Recent studies have shown that inappropriate activation of STATs occurs frequently in a wide variety of human cancers. Here we examine the functional status of Stat5 proteins in SzS as compared with healthy donors. Western blotting demonstrates that in cytoplasmic extracts of unstimulated T cells from healthy controls two isoforms of Stat5, full-length and a COOH-terminal truncated isoform, termed Stat5(t), are present. However, bandshift assays demonstrate that only Stat5(t) translocates to the nucleus and binds DNA on IL-2 stimulation. In contrast, preactivated T cells express only full-length Stat5, which is functionally activated on IL-2 stimulation. Analysis of Stat5 protein isoforms from five of five SzS patients revealed predominant aberrant expression of Stat5(t) in preactivated peripheral blood mononuclear cell. Furthermore, patients showed preferential IL-2-induced DNA binding of Stat5(t). Consistent with the inappropriate activation of Stat5(t) in SzS patients, real-time PCR revealed that IL-2-induced mRNA expression of the Stat5 target genes, Bcl-2, PIM-1, and CISH were markedly reduced. These data indicate that functional Stat5 isoform expression is regulated by T-cell activation status and that dysregulated expression of Stat5(t) in malignant T cells in SzS can suppress Stat5-dependent gene expression. Thus, aberrant expression of Stat5(t) may be one mechanism that contributes to the cellular transformation of T cells in this disease.
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PMID:Dysregulated expression of COOH-terminally truncated Stat5 and loss of IL2-inducible Stat5-dependent gene expression in Sezary Syndrome. 1469 24

Our current focus on the effects of Photodynamic Therapy (PDT) using silicon phthalocyanine Pc 4 photosensitizer on malignant T lymphocytes arose due to preclinical observations that Jurkat cells, common surrogate for human T cell lymphoma, were more sensitive to Pc 4-PDT-induced killing than epidermoid carcinoma A431 cells. Mycosis fungoides (MF) as well as Sezary syndrome (SS) are variants of cutaneous T-cell lymphoma (CTCL) in which malignant T-cells invade the epidermis. In this study, we investigated the cytotoxicity of Pc 4-PDT in peripheral blood cells obtained from patients with SS and in skin biopsies of patients with MF. Our data suggest that Pc 4-PDT preferentially induces apoptosis of CD4(+)CD7(-) malignant T-lymphocytes in the blood relative to CD11b(+) monocytes and nonmalignant T-cells. In vivo Pc 4-PDT of MF skin also photodamages the antiapoptotic protein Bcl-2.
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PMID:Photodynamic therapy with the silicon phthalocyanine pc 4 induces apoptosis in mycosis fungoides and sezary syndrome. 2119 3

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.
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PMID:Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. 2208 Apr 80