Bcl-2 and the ICE family of apoptotic regulators: making a connection

doi:10.1016/S0959-437X(97)80109-8

Current Opinion in Genetics & Development

Volume 7, Issue 1, February 1997, Pages 52-58

https://doi.org/10.1016/S0959-437X(97)80109-8 Get rights and content

Abstract

Apoptosis, a genetically programmed mechanism of eliminating cells in response to a variety of stimuli, provides protection against cancer and viral infections as well as maintenance of homeostasis in living organisms. Two classes of molecules, the Bcl-2 family of regulators and the ICE family of proteases, have emerged from different vertebrate, invertebrate and viral systems that have been used to elucidate the pathways leading to apoptosis. However, no connection between these two disparate families of apoptotic regulators has been convincingly established. In reviewing the recent advances pertaining to the Bcl-2 and ICE-related protein families, one can address the question of a functional relationship between the two classes of proteins.

References (60)

H Ellis et al.
Genetic control of programmed cell death in in the nematode C. elegans
Cell
(1986)
HM Ellis et al.
Mechanisms and functions of cell death
Annu Rev Cell Biol
(1991)
J Han et al.
The E1B 19K protein functions as an apoptosis inhibitor by interacting with and inhibiting the p53-inducible and death-promoting Bax protein
Genes Dev
(1996)
JM Boyd et al.
Bik1, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins
Oncogene
(1995)
A Fraser et al.
A license to kill
Cell
(1996)
NJ Bump et al.
Inhibition of ICE family proteases by baculovirus anti-apoptotic protein p35
Science
(1995)
Y Lazebnik et al.
Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution
Proc Natl Acad Sci USA
(1995)
M Tewari et al.
Recent advances in tumor necrosis factor and CD40 signaling
Curr Opin Genet Dev
(1996)
M Muzio et al.
FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex
Cell
(1996)
MP Boldin et al.
Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1 and TNF receptor-induced cell death
Cell
(1996)

YA Lazebnik et al.

Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE

Nature

(1994)

Z-Q Wang et al.

Mice lacking ADPRT and poly(ADP) ribosylation develop normally but are susceptible to skin disease

Genes Dev

(1995)

L Rao et al.

Lamin proteolysis facilitates nuclear events during apoptosis

J Cell Biol

(1996)

A Takahashi et al.

Cleavage of lamin A by Mch2α but not CPP32: multiple ICE-related proteases with distinct substrate recognition properties are active in apoptosis

Proc Natl Acad Sci US

(1996)

CA Boulakia et al.

Bcl-2 and adenovirus E1B 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase

Oncogene

(1996)

A Bakhshi et al.

Cloning the chromosomal break-point of the t(14:18) human lymphomas; clustering around JH on Chromosome 14 and near a transcriptional unit on 18

Cell

(1985)

Y Tsujimoto et al.

The t(14;18) chromosome translocations involved in B cell neoplasms result from mistakes in VDJ joining

Science

(1985)

ML Cleary et al.

Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active loucus on chromosome 18

Proc Natl Acad Sci USA

(1985)

G Nuez et al.

Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines

J Immunol

(1990)

DL Vaux et al.

Bcl-2 promotes the survival of haemopoietic cells and coopeerates with c-myc to immortalize pre-B cells

Nature

(1988)

E White

Life, death, and the pursuit of apoptosis

Genes Dev

(1996)

ZN Oltvai et al.

Bcl-2 heterodimerizes in vivo with a conserved homolog. Bax, that accelerates programmed cell death

Cell

(1993)

ZN Oltavi et al.

Checkpoints of dueling dimers foil death wishes

Cell

(1994)

X-M Yin et al.

BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax

Nature

(1994)

J Yuan et al.

The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme

Cell

(1993)

K-I Nakayama et al.

Disappearance of the lymphoid system in bcl-2 homozygous mutant chimeric mice

Science

(1993)

S Kamada et al.

Bcl-2 deficiency in mice leads to pleiotropic abnormalities; accelerated lymphoid cell death in the thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine

Cancer Res

(1995)

CM Knudson et al.

Bax-deficient mice demonstrate lympoid hyperplasia but male germ cell death

Science

(1995)

K Nakayama et al.

Targeted disruption of bcl-2 alpha beta in mice — occurrence of grey hair, polycystic kidney disease, and lymphocytopenia

Proc Natl Acad Sci USA

(1994)

T Chittenden et al.

Induction of apoptosis by the Bcl-2 homologue Bak

Nature

(1995)

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Bcl-2 and the ICE family of apoptotic regulators: making a connection

Abstract

Cell

Annu Rev Cell Biol

Genes Dev

Oncogene

Cell

Science

Proc Natl Acad Sci USA

Curr Opin Genet Dev

Cell

Cell

Nature

Genes Dev

J Cell Biol

Proc Natl Acad Sci US

Oncogene

Cloning the chromosomal break-point of the t(14:18) human lymphomas; clustering around JH on Chromosome 14 and near a transcriptional unit on 18

Cell

The t(14;18) chromosome translocations involved in B cell neoplasms result from mistakes in VDJ joining

Science

Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active loucus on chromosome 18

Proc Natl Acad Sci USA

Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines

J Immunol

Bcl-2 promotes the survival of haemopoietic cells and coopeerates with c-myc to immortalize pre-B cells

Nature

Life, death, and the pursuit of apoptosis

Genes Dev

Bcl-2 heterodimerizes in vivo with a conserved homolog. Bax, that accelerates programmed cell death

Cell

Checkpoints of dueling dimers foil death wishes

Cell

BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax

Nature

The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme

Cell

Disappearance of the lymphoid system in bcl-2 homozygous mutant chimeric mice

Science

Bcl-2 deficiency in mice leads to pleiotropic abnormalities; accelerated lymphoid cell death in the thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine

Cancer Res

Bax-deficient mice demonstrate lympoid hyperplasia but male germ cell death

Science

Targeted disruption of bcl-2 alpha beta in mice — occurrence of grey hair, polycystic kidney disease, and lymphocytopenia

Proc Natl Acad Sci USA

Induction of apoptosis by the Bcl-2 homologue Bak

Nature