J C Martinou — Page 5 | Search PubMed

PubMedDate not supplied

Mitochondria: regulating the inevitable.

Apoptosis is a form of programmed cell death important in the development and tissue homeostasis of multicellular organisms. Abnormalities in cell death control can lead to a variety of diseases, including cancer and degenerative disorders. Hence, the process of apoptosis is tightly regulated through multiple independent signalling pathways that are initiated either from triggering events within the cell or at the cell surface. In recent years, mitochondria have emerged as the central components of such apoptotic signalling pathways and are now known to control apoptosis through the release of apoptogenic proteins. In this review we aim to give an overview of the role of the mitochondria during apoptosis and the molecular mechanisms involved.

Apoptosis↗

PubMedDate not supplied

Dissection of functional domains in Bcl-2 alpha by site-directed mutagenesis.

Bcl-2 alpha is a mitochondrial or perinuclear-associated oncoprotein that prolongs the life span of a variety of cell types by interfering with programmed cell death. How Bcl-2 confers cell survival is unknown, although antioxidant and antiprotease functions have been proposed. In addition, protein structures of Bcl-2 that are crucial for its survival activity are still ill-defined. Bcl-2 can occur as Bcl-2 alpha or Bcl-2 beta, two alternatively spliced forms which solely differ in their carboxyl termini. The finding that Bcl-2 alpha is active and membrane bound, but Bcl-2 beta is inactive and cytosolic, indicates that the carboxyl terminus contributes to the survival activity of Bcl-2. This region contains two subdomains, a domain X with unknown function and a hydrophobic stretch reported to mediate membrane association of Bcl-2 alpha. Recently Bcl-2-related proteins have been identified. These include Bax that heterodimerizes with Bcl-2 and, when overexpressed, counteracts Bcl-2. Bax contains two highly conserved regions of sequence homology with Bcl-2, referred to as Bcl-2 homology 1 and 2 (BH1 and BH2) domains. Site-directed mutagenesis studies have revealed that both domains are not only novel dimerization motifs for the interaction of Bax with Bcl-2 but also crucial for the survival activity of Bcl-2. Interestingly, the C-terminal end of BH2 encompasses the Bcl-2 alpha/beta splice site, as well as part of domain X in Bcl-2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗