242
Mohamed Al-Rubeai
majoirty of follicular lymphomas. Originally it was found that bcl-2 promoted
the survival, but not proliferation of IL-3 dependent myeloid cell lines after the
removal of IL-3 [75]. Moreover, transgenic mice expressing bcl-2 develop
follicular hyperplasia with large excess of B lymphocytes with enhanced survival
[76]. Further studies have shown that bcl-2 inhibits apoptosis in a variety of cell
types in response to a variety of signals including chemothrapeutic drugs, ionizing
radiation, cytotoxic lymphokines, growth factor deprivation, nutrient depletion,
hyperoxia, hypoxia and some viruses. However, its inhibitory effect on apoptosis
is not universal, as it has been shown that it does not prevent apoptosis induced
by a variety of triggers including cytotoxic T-lymphocytes [77, 78].
The precise molecular function of bcl-2 remains unclear. It has been suggested
that the association between bcl-2 and the 23 kDa p23 R-ras gene product may
indicate a possible role of this member of the ras gene family in the regulation of
apoptosis [79]. Studies on human breast cancer have indicated that p53 can
down regulate the expression of bcl-2 [80], but it can upregulate the expression
of bax which encodes a dominant inhibitor of the bcl-2 protein that forms
heterodimers with it [81]. It is probable that the ratio of Bcl-2 to Bax proteins
may predetermine the apoptotic response of some cells to death triggers - higher
Bcl-2 leads to survival while higher Bax leads to death [82].
Bax is a member of the Bcl-2 extended family of proteins that also includes
bcl-Xs, bcl-XL, Bad, Bak and Mcl-1. Very little is known about the interaction
among these proteins but their increasing number and their functional similarities suggest that there may be a duplication of function and a common molecular
pathway that controls the suppression or predisposition of mammalian cells to
apoptosis.
The localisation of the bcl-2 gene at several intracellular sites including the
nuclear membrane, endoplasmic reticulum, mitochondrial and plasma membrane and the subsequent aggregation under stressed conditions suggest that
bcl-2 might target itself to specific sites following the exposure of the cell to an
apoptotic inducing agent [83]. It has been suggested that the principal product
of bcl-2, which is a 26 kDa integral membrane protein containing a stretch of
hydrophobic amino acids at the carboxyl terminus, is used for post-translational
insertion into the cellular membrane [84].
Hockenbery et al. [85] and Kane et al. [86] proposed that apoptosis
involves the generation of reactive oxygen species and that the survival enhancing activity of bcl-2 may be mediated through an oxidative pathway. This idea
was suggested because of the belief that many of the agents that trigger
apoptosis generate reactive oxygen species and that superoxide ion and H202
are produced mainly around mitochondria where bcl-2 is predominantly
located. However, several recent studies provided evidence against this hypothesis showing that reactive oxygen species are not a central part of the apoptotic
regulatory pathways [87, and Cotter TG, personal communication]. Furthermore, recent data suggests that bcl-2 exerts its anti-apoptotic activity by a mechanism that does not involve oxidative reactive pathways [87-89, and our
unpublished results].
Mohamed Al-Rubeai
majoirty of follicular lymphomas. Originally it was found that bcl-2 promoted
the survival, but not proliferation of IL-3 dependent myeloid cell lines after the
removal of IL-3 [75]. Moreover, transgenic mice expressing bcl-2 develop
follicular hyperplasia with large excess of B lymphocytes with enhanced survival
[76]. Further studies have shown that bcl-2 inhibits apoptosis in a variety of cell
types in response to a variety of signals including chemothrapeutic drugs, ionizing
radiation, cytotoxic lymphokines, growth factor deprivation, nutrient depletion,
hyperoxia, hypoxia and some viruses. However, its inhibitory effect on apoptosis
is not universal, as it has been shown that it does not prevent apoptosis induced
by a variety of triggers including cytotoxic T-lymphocytes [77, 78].
The precise molecular function of bcl-2 remains unclear. It has been suggested
that the association between bcl-2 and the 23 kDa p23 R-ras gene product may
indicate a possible role of this member of the ras gene family in the regulation of
apoptosis [79]. Studies on human breast cancer have indicated that p53 can
down regulate the expression of bcl-2 [80], but it can upregulate the expression
of bax which encodes a dominant inhibitor of the bcl-2 protein that forms
heterodimers with it [81]. It is probable that the ratio of Bcl-2 to Bax proteins
may predetermine the apoptotic response of some cells to death triggers - higher
Bcl-2 leads to survival while higher Bax leads to death [82].
Bax is a member of the Bcl-2 extended family of proteins that also includes
bcl-Xs, bcl-XL, Bad, Bak and Mcl-1. Very little is known about the interaction
among these proteins but their increasing number and their functional similarities suggest that there may be a duplication of function and a common molecular
pathway that controls the suppression or predisposition of mammalian cells to
apoptosis.
The localisation of the bcl-2 gene at several intracellular sites including the
nuclear membrane, endoplasmic reticulum, mitochondrial and plasma membrane and the subsequent aggregation under stressed conditions suggest that
bcl-2 might target itself to specific sites following the exposure of the cell to an
apoptotic inducing agent [83]. It has been suggested that the principal product
of bcl-2, which is a 26 kDa integral membrane protein containing a stretch of
hydrophobic amino acids at the carboxyl terminus, is used for post-translational
insertion into the cellular membrane [84].
Hockenbery et al. [85] and Kane et al. [86] proposed that apoptosis
involves the generation of reactive oxygen species and that the survival enhancing activity of bcl-2 may be mediated through an oxidative pathway. This idea
was suggested because of the belief that many of the agents that trigger
apoptosis generate reactive oxygen species and that superoxide ion and H202
are produced mainly around mitochondria where bcl-2 is predominantly
located. However, several recent studies provided evidence against this hypothesis showing that reactive oxygen species are not a central part of the apoptotic
regulatory pathways [87, and Cotter TG, personal communication]. Furthermore, recent data suggests that bcl-2 exerts its anti-apoptotic activity by a mechanism that does not involve oxidative reactive pathways [87-89, and our
unpublished results].