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MINI-REVIEW Programmed Cell Death Regulation Leukemia (2000) 14, 1340–1344 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu MINI-REVIEW Programmed cell death regulation: basic mechanisms and therapeutic opportunities DE Johnson Departments of Medicine and Pharmacology, University of Pittsburgh, and the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA The molecular mechanisms responsible for induction or inhi- pH changes during apoptosis bition of apoptosis signal transduction have been intensively investigated during the past few years. Information gained from mechanistic studies and from structural analysis of apoptosis With respect to regulation of intracellular pH during regulatory proteins has provided considerable insight into the apoptosis, Dr Roberta Gottlieb reported that neutrophils pathways that determine whether a cell will live or die. Many deprived of G-CSF exhibit rapid cytosolic acidification, with of these advances were recently presented at the American cells typically reaching a pH of 6.6. Similar results were seen Association for Cancer Research Special Conference on ‘Pro- in Jurkat T leukemic cells undergoing Fas-mediated grammed Cell Death Regulation: Basic Mechanisms and Thera- apoptosis.1 Acidification was found to be concurrent with peutic Opportunities’. This mini-review will discuss the current state of knowledge regarding apoptosis signaling pathways phosphatidyl serine (PS) externalization, and it was proposed and the function of apoptosis regulatory proteins. Leukemia that the pH sensitivity of the enzyme responsible for flipping (2000) 14, 1340–1344. PS may account for this commonly observed apoptotic event. Keywords: apoptosis; mitochondria; Bcl-2; caspase; IAP; TRAIL Dr Gottlieb also observed that cytoplasmic acidification pre- cedes loss of mitochondrial membrane potential, and can be blocked by expression of Bcl-2. Dr John Reed reported some- Introduction what similar findings, noting that staurosporin can induce a rapid rise in mitochondrial pH which precedes both cyto- Nestled amid towering Ponderosa Pines on the shores of chrome c release and loss of mitochondrial membrane poten- scenic Lake Tahoe, 390 scientists gathered between 27 Febru- tial. Proapoptotic Bax protein induced cytosolic acidification, ary and 2 March for the American Association for Cancer and this could be blocked by oligomycin, which inhibits the Research Special Conference on ‘Programmed Cell Death mitochondrial FoF1-ATPase proton pump.2 Dr Reed also Regulation: Basic Mechanisms and Therapeutic Opportunit- showed that acidic pH enhances cytochrome c-dependent ies’. Organizers of the conference were Dr John C Reed (The caspase activation, suggesting how a change in cytosolic pH Burnham Institute, La Jolla, CA, USA) and Dr Junying Yuan may further the course of apoptotic execution. In related stud- (Harvard University, Cambridge, MA, USA). The conference ies, Dr Donald Nicholson concluded that changes in pH may provided greater clarity and understanding regarding many facilitate the processing and activation of executioner casp- issues in the field of apoptosis, while raising new questions ases such as caspase-3 (discussed below). Together, these and suggesting new directions. The tenor for the meeting was findings indicate that intracellular pH changes are an early set by keynote speaker Dr Andrew Wyllie (University of Cam- event during apoptosis, and may play important roles in driv- bridge, Cambridge, UK) who reviewed ‘where we have come ing subsequent biochemical changes associated with the from’, then asked ‘where are we going?’. In rhetorical death process. response, Dr Wyllie raised several questions that are awaiting answers: what is the linkage between cytochrome c release, Bcl-2 family members and Apaf-1? What are the intracellular Role of mitochondria and cytochrome c release sites for apoptosis signaling? Are locations other than mito- chondria, cytoplasm and nucleus important? Which caspase Mitochondria are likely to be important sites for the regulation substrates are critically important for death? Are there alterna- of cellular pH during apoptosis. However, these organelles tives to caspase-mediated death? How does p53 activation also contain other biochemical components which are critical feed into apoptosis? In addition to these topics, other issues to the death of the cell. It is well established that during receiving considerable attention during the conference apoptosis cytochrome c is released by the mitochondria into included the role of intracellular pH changes and the roles of the cytoplasm, where it facilitates the initiation of a caspase mitochondria and endoplasmic reticulum during apoptosis; cascade.3–5 Dr Craig Thompson, however, challenged the the molecular mechanisms of caspase activation; the notion that caspases are the sole mediator of cell death. He expression and function of inhibitor of apoptosis proteins noted that caspase inhibitors, while able to block morphologic (IAPs); the structure of functional domains in apoptosis sig- changes during apoptosis, only serve to delay eventual cell naling molecules; the identification of novel apoptosis sig- death. He proposed that changes in mitochondrial bioenerget- naling proteins; and the potential for clinical benefit from ics may ultimately be responsible for the death of the cell. apoptosis research. Dr Thompson reported that during apoptosis induced by IL-3 withdrawal, cytoplasmic ATP levels plummet due to impair- ment of ATP/ADP exchange across the mitochondrial outer membrane.6 The impairment of this exchange could be pre- Correspondence: DE Johnson, Division of Hematology/Oncology, vented by overexpression of Bcl-X . In cells that do undergo Department of Medicine, University of Pittsburgh, Biomedical Science L Tower, Room BST E1055, 211 Lothrop Street, Pittsburgh, PA, 15213– apoptosis, voltage-dependent anion channel (VDAC), located 2582, USA; Fax: (412) 624–7794 in the outer mitochondrial membrane and a component of the Received 22 March 2000; accepted 3 April 2000 mitochondrial permeability transition pore, is maintained in a Mini-review DE Johnson 1341 closed configuration, preventing ATP/ADP exchange (via the gators, including Drs Suzanne Cory, Nunez and Reed reported carriers creatine–phosphate/creatine) across the membrane. that in mammalian systems Bcl-2 does not appear to bind to Bcl-XL was found to maintain VDAC in an open configuration, Apaf-1 protein. It was proposed that there may be other, yet allowing exchange even in the presence of an apoptotic to be discovered, mammalian homologs of Apaf-1 which are stimulus.6 able to bind to Bcl-2. Interestingly, Drs Nunez and Michael The mechanism of cytochrome c release by mitochondria Hengartner reported that in C. elegans, CED-9 forms a com- was addressed by Drs Reed and Stanley Korsmeyer. Previous plex with CED-4, and this complex can be disrupted by EGL- studies have proposed that during apoptosis mitochondria 1, a proapoptotic, BH3 domain-containing protein.12–14 swell, leading to rupture of the outer mitochondrial membrane According to Dr Nunez, mutants of CED-9 which bind EGL- and subsequent release of cytochrome c.7 Dr Reed stated that 1, but fail to release CED-4, abrogate downstream activation this is not a likely mechanism for cytochrome c release, since of CED-3 protease, indicating that CED-4 release is necessary cytochrome c release precedes mitochondrial swelling during for the protease activation. Additional insights into apopto- staurosporin-induced apoptosis. Moreover, his laboratory has some function will likely come from Drosophila; Drs John found that Bax-induced cytochrome c release occurs in the Abrams and Hermann Steller reported on the discovery of a absence of swelling. Dr Korsmeyer suggested that oligomeriz- Drosophila Apaf-1 homolog termed DARK or HAC-1.15 ation of proapoptotic proteins such as Bax or Bak in the mito- chondrial outer membrane may generate pores with sufficient openings to allow release of cytochrome c. The laboratories Other subcellular sites of apoptosis signal transduction of Drs Xiaodong Wang and Junying Yuan have previously shown that stimulation of cell surface death receptors leads While mitochondria, cytoplasm, and nucleus clearly are to caspase-8-dependent cleavage of Bid protein, which then important locations for apoptosis signal transduction, translocates to the mitochondria and promotes cytochrome c increased attention is being paid to other subcellular sites. In release.8,9 Dr Korsmeyer reported that cleaved Bid facilitates particular, emerging evidence suggests important roles for pro- the oligomerization of Bak in the outer mitochondrial mem- teins associated with the endoplasmic reticulum. Dr Gordon brane. Moreover, in artificial lipid membranes, his group Shore discussed the cloning of a novel protein, BAP31, iso- found that homotetramers of Bax protein produced sufficient lated in a screen for Bcl-2 binding proteins.16 BAP31 is pore sizes to allow the passage of cytochrome c-sized mol- localized exclusively in the endoplasmic reticulum, with an ecules through the membrane. He proposed that oligomers of N-terminus facing the lumen, three transmembrane domains, Bak, Bax, or similar molecules may serve as pores for release and a C-terminal death effector domain (DED). In addition to of cytochrome c. its ability to bind Bcl-2, BAP31 also binds caspase-8. Caspase- 8 can cleave BAP31, and the cleavage product is potently pro- apoptotic. In contrast, overexpression of a noncleavable Apoptosome structure and function BAP31
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