Search results for "BCL-2 FAMILY"
showing 4 items of 14 documents
Differences in the Association of BH3-Only Proteins to Biological Membranes
2017
Apoptosis, a prevalent mechanism of programmed cell death, is regulated by the Bcl-2 protein family. The balance between pro- and anti-apoptotic Bcl-2 members in the mitochondrial outer membrane (MOM) protects or triggers MOM permeabilization. Bcl-2 homology-3 (BH3)-only proteins participate in this process activating pro-apoptotic effectors and promoting permeabilization of the MOM. The membrane association of BH3-only proteins is controversial due to the lack of a canonical carboxyl-terminal (C-terminal) transmembrane (TM) domain. We used an in vitro transcription/translation system to study the insertion capacity of these hydrophobic C-terminal regions of the BH3-members Bik, Bim, Noxa, …
Permeabilization of the Outer Mitochondrial Membrane by Bcl-2 Proteins
2010
The proteins of the Bcl-2 family regulate the release of the apoptotic factors from mitochondria during apoptosis, a key event in physiological cell death. Although their molecular mechanisms remain unclear, the Bcl-2 proteins have been proposed to directly control the permeability of the outer mitochondrial membrane by pore formation. Indeed, they share structural features with the pore forming domains of some bacterial toxins and they can give rise to proteolipidic pores in model membranes. The complex level of regulation needed to decide the fate of the cell is achieved by an intricate interaction network between different members of the family. Current models consider multiple parallel …
Conformational control of Bax localization and apoptotic activity by Pro168.
2004
In healthy cells, Bax resides inactive in the cytosol because its COOH-terminal transmembrane region (TMB) is tucked into a hydrophobic pocket. During apoptosis, Bax undergoes a conformational change involving NH2-terminal exposure and translocates to mitochondria to release apoptogenic factors. How this process is regulated remains unknown. We show that the TMB of Bax is both necessary and sufficient for mitochondrial targeting. However, its availability for targeting depends on Pro168 located within the preceding loop region. Pro168 mutants of Bax lack apoptotic activity, cannot rescue the apoptosis-resistant phenotype of Bax/Bak double knockout cells, and are retained in the cytosol even…
Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis.
2008
The chimeric monoclonal antibody rituximab is the standard of care for patients with B-cell non-Hodgkin lymphoma (B-NHL). Rituximab mediates complementdependent cytotoxicity and antibodydependent cellular cytotoxicity of CD20-positive human B cells. In addition, rituximab sensitizes B-NHL cells to cytotoxic chemotherapy and has direct apoptotic and antiproliferative effects. Whereas expression of the CD20 antigen is a natural prerequisite for rituximab sensitivity, cell-autonomous factors determining the response of B-NHL to rituximab are less defined. To this end, we have studied rituximab-induced apoptosis in human B-NHL models. We find that rituximab directly triggers apoptosis via the m…