(Tetrahymena proliferation-activating factor, TPAF) has been isolated and shown to
enhance survival at low cell density (Schousboe et al., 1998). Insulin-like signals have
also been shown to prevent cell death in Tetrahymena cultures (Christensen et al.,
1996). Despite the apparent similarity in survival signaling between Tetrahymena and
higher eukaryotes, the phenotype of dying cells is quite different in Tetrahymena.
3.3
Programmed cell death in TrypanosomaThe last example of programmed cell death in single-celled eukaryotes that we
consider concerns members of the Kinetoplastids, the parasites Trypanosoma and
Leishmania, which cause disease in animals and man (Chagas’ disease, African sleeping
sickness, and kala azar). Kinetoplastids take their name from a giant mitochondrium,
the kinetoplast, which is present in all members of this group. The life cycle of
Trypanosoma involves alternation of hosts from insects to mammals. Epimastigotes
are the proliferating stage of trypanosomes in the insect host. They differentiate into
trypomastigotes that are arrested at G0/G1 and are transmitted to the vertebrate host.
Here they differentiate into amastigotes that resume proliferation.
When the differentiation of epimastigotes into trypomastigotes was investigated
in cell culture, it was observed that only a minority of epimastigotes were arrested at
G0/G1 and differentiated into trypomastigotes. The majority under-went cell death
that showed typical features of mammalian apoptosis, including TUNEL staining,
DNA fragmentation into nucleosome-sized pieces, membrane blebbing, and
cytoplasmic vacuolization (Ameisen et al., 1995). This form of programmed cell death
is dependent on extracellular (autocrine) signals and has been interpreted as a means
for epimastigotes to adjust their numbers in the insect host to levels that permit
differentiation while ensuring the survival of the host. Similar observations were made
with promastigotes of Leishmania (Moreira et al., 1996) and with epimastigotes of
Trypanosoma brucei rhodesiense (Welburn et al., 1999).
Inhibitors of RNA and protein synthesis block cell death in trypanosomes,
indicating that cell death requires de novo gene expression. Using a differential display
method, Welburn et al. identified genes that were expressed in cells induced to die.
Among those genes was a homolog of TRACK, a receptor for PKC, and a serine/
threonine kinase, suggesting that cell-cell signaling could be involved in regulation
of programmed cell death in Trypanosoma. A number of mitochondrial genes were
also induced in cells during programmed cell death, including a mitochondrial RNA
splicing protein, a mitochondrial transporter, cytochrome c, and prohibitin, a
mitochondrial protein involved in cell-cycle regulation and tumor suppression
(Welburn and Murphy, 1998).
These are all very interesting findings that may help to elucidate apoptotic
mechanisms that arose very early in evolution. However, a complete picture is lacking
at the moment. The difficulty in interpreting data relating to apoptosis in parasites
in terms of evolution arises because these organisms are the result of a long process
of adaptation to their multicellular hosts. For example, it has been shown that parasites
EVOLUTION OF CELL DEATH 159