Fas-deficient (Fas(lpr/lpr)) mice constitutively expressing Bcl-2 in myeloid cells by the hMRP8 promoter often develop a fatal disease analogous to human acute myeloblastic leukemia (AML-M2). Hematopoietic cells from leukemic Fas(lpr/lpr)hMRP8bcl-2 animals form clonogenic blast colonies in vitro and can transfer disease to wild-type mice. In vitro ligation of Fas on Fas+/+ hMRP8bcl-2 marrow cells depletes approximately 50% of myeloid progenitor activity, demonstrating that Bcl-2 can only partially block Fas-mediated death signals in myelomonocytic progenitors. In addition, Fas(lpr/lpr) marrow contains greatly increased numbers of myeloid colony-forming cells as compared to Fas+/+ controls. Taken together, these data suggest that Fas has a novel role in the regulation of myelopoiesis and that Fas may act as a tumor suppressor to control leukemogenic transformation in myeloid progenitor cells.
"Among the important molecules that affect the intrinsic apoptotic pathway through mitochondria, the Bcl-2 family proteins play a major role in cell survival and drug sensitivity since dysregulation of Bcl-2 family is often observed in various types of human cancer, including renal, ovarian, stomach, and brain tumors and leukemia [106–108]. It has been shown that increased expression of prosurvival Bcl-2 homologues  or lack of BH3-only protein expression and/or function (e.g., caused by loss of p53)  contributed to tumorigenesis and anticancer drug resistance. "
[Show abstract][Hide abstract] ABSTRACT: Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.
The Scientific World Journal 03/2014; 2014:604685. DOI:10.1155/2014/604685 · 1.73 Impact Factor
"Thus, our observations strongly support the etiological relevance of cebpa mutations in patients who have AML, and inhibition of C/EBPα function by translocation products found in myeloid leukemias. Previously, induction of AML-like disease in vivo by expression of PML-RARα or BCR-ABL transgenes (34–36), by ectopic Bcl-2 expression combined with the absence of Fas signaling (37), and by ectopic AML-ETO expression in conjunction with N-ethyl-N′-nitrosourea mutagenesis (38, 39) has been observed. However, the precise mechanisms of action of translocation-derived oncoproteins remain unclear, not least because each transgenically expressed oncoprotein generally affects several cellular targets, in the case of AML-ETO and BCR-ABL including C/EBPα. "
[Show abstract][Hide abstract] ABSTRACT: CCAAT/enhancer binding protein (C/EBP)alpha is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBP alpha to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations--all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count--normally associated with AML-were absent. These results show that disrupting the cell cycle regulatory function of C/EBP alpha is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.
Journal of Experimental Medicine 08/2005; 202(1):85-96. DOI:10.1084/jem.20050067 · 12.52 Impact Factor
"Not only defects in the Bcl-2-regulated apoptosis signalling pathway but also abnormalities in 'death receptor' signalling can cause disease . For example, loss of function of Fas   , its ligand, FasL , or its essential signal transducer FADD/MORT1  can all cause lymphadenopathy , autoimmune disease and/or haematological malignancy. "
[Show abstract][Hide abstract] ABSTRACT: Seminal studies on the proto-oncogene bcl-2 have first demonstrated that mutations that inhibit programmed cell death (apoptosis) can promote lymphomagenesis and influence the sensitivity of tumour cells to chemotherapy or radiotherapy. It is now widely believed that neoplastic transformation of many, perhaps even all, cell types requires mutational changes that interfere with the cell death programme. In this review, we describe current knowledge of the molecular control of cell death and discuss the role of pro- and anti-apoptotic members of the Bcl-2 protein family in tumourigenesis and anti-cancer therapy.
Seminars in Cancer Biology 05/2003; 13(2):115-23. DOI:10.1016/S1044-579X(02)00129-3 · 9.33 Impact Factor
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