Consistently, in a yeast mutant lacking P5C dehydrogenase, proline leads to growth
inhibition and formation of ROS. P5C dehydrogenase is expressed at a basal level in
all tissues analyzed, in agreement with a protective role against cell death (Deuschle
et al., 2001).
9.
Applications of yeast apoptosis for medical researchThe spread of HIV infection and the increasing number of patients treated with
immunosuppressive drugs have caused infections by opportunistic fungi to flourish.
The yeast Candida albicans, otherwise part of the normal human flora, has become
a pathogen commonly causing systemic infections. Helmerhorst et al. (2001) found
that the human salivary antifungal peptide histatin 5 kills Candida by induction of
oxygen stress. The human salivary peptide histatin 5 exerts its antifungal activity
through the formation of ROS. Indeed, Candida exhibits an apoptotic phenotype in
response to classical metazoan apoptosis inducers (Mark Ramsdale, personal
communication). The potential for apoptosis in Candida might lead to a new class
of drugs against fungal infections.
In a recent review, Zhao and Elder (2000) summarize the contribution of research
on yeast to the molecular understanding of HIV infection. Increasing evidence
suggests that the HIV-1 viral protein R (Vpr) plays an important role in viral
pathogenesis, as its functions are being linked to viral activation, suppression of
human immune functions, and depletion of human CD4 lymphocytes, the major
clinical manifestation of AIDS. In vitro, Vpr shows multiple activities in both
mammalian and yeast cells, including nuclear transport, induction of cell-cycle G2
arrest, morphologic changes, and cell death. The occurrence of these activities in yeast
indicates that Vpr interacts with highly conserved cellular processes to cause the
effects, and allows Vpr activities to be studied in these genetically well-characterized
organisms. Studies of Vpr in S.pombe and S.cerevisiae have helped to establish the
following milestones: (i) Vpr induces G 2 arrest through inhibitory phosphorylation
of the cyclin-dependent kinase by a pathway in which protein phosphatase 2A plays
an important role. (ii) Vpr induces apoptosis by directly permeabilizing the
mitochondrial membrane. (iii) Vpr also appears to kill cells by mitochondria-
independent mechanisms. (iv) G 2 arrest and cell death induced by Vpr are two
independent functions. Future studies of Vpr in yeast are expected to make additional
contributions to understanding the mechanisms of Vpr activities and may also help
address the importance of these activities during the course of HIV-1 infection (Zhao
et al., 1998; Elder et al., 2001).
REGULATORS AND APPLICATIONS OF YEAST APOPTOSIS 149