David C.S. Huang

Bio: David C.S. Huang is an academic researcher from Walter and Eliza Hall Institute of Medical Research. The author has contributed to research in topics: Programmed cell death & Apoptosis. The author has an hindex of 90, co-authored 268 publications receiving 37506 citations. Previous affiliations of David C.S. Huang include Royal Children's Hospital & Royal Melbourne Hospital.

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

Abstract: Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.

Abstract: Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells and succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic stimuli such as cytokine deprivation, calcium ion flux, and microtubule perturbation but not to others. Thus, Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli appear to activate apoptosis through distinct BH3-only proteins.

The Bcl-2 family: roles in cell survival and oncogenesis.

Abstract: Apoptosis, the cell-suicide programme executed by caspases, is critical for maintaining tissue homeostasis, and impaired apoptosis is now recognized to be a key step in tumorigenesis. Whether a cell should live or die is largely determined by the Bcl-2 family of anti- and proapoptotic regulators. These proteins respond to cues from various forms of intracellular stress, such as DNA damage or cytokine deprivation, and interact with opposing family members to determine whether or not the caspase proteolytic cascade should be unleashed. This review summarizes current views of how these proteins sense stress, interact with their relatives, perturb organelles such as the mitochondrion and endoplasmic reticulum and govern pathways to caspase activation. It briefly explores how family members influence cell-cycle entry and outlines the evidence for their involvement in tumour development, both as oncoproteins and tumour suppressors. Finally, it discusses the promise of novel anticancer therapeutics that target these vital regulators.

Proapoptotic Bak Is Sequestered by Mcl-1 and Bcl-xL, but Not Bcl-2, Until Displaced by BH3-only Proteins

Abstract: How the Bcl-2 family of proteins regulate programmed cell death triggered by developmental cues and in response to multiple stress signals is of intense interest (Adams 2003; Danial and Korsmeyer 2004). Whereas cell survival is promoted by Bcl-2 itself and several close relatives (Bcl-xL, Bcl-w, Mcl-1, and A1), which bear three or four conserved Bcl-2 homology (BH) regions, apoptosis is driven by two other subfamilies. The initial signal for cell death is conveyed by the diverse group of BH3-only proteins, including Bad, Bid, Bim, Puma, and Noxa, which have in common only the small BH3 interaction domain (Huang and Strasser 2000). However, Bax or Bak (multidomain proteins containing BH1-BH3) are required for commitment to cell death (Lindsten et al. 2000; Cheng et al. 2001; Wei et al. 2001; Zong et al. 2001). When activated, they can permeabilize the outer membrane of mitochondria and release proapoptogenic factors (e.g., cytochrome c) needed to activate the caspases that dismantle the cell (Adams 2003; Danial and Korsmeyer 2004; Green and Kroemer 2004). Interactions between members of these three factions of the Bcl-2 family dictate whether a cell lives or dies. When BH3-only proteins have been activated, for example, in response to DNA damage, they can bind via their BH3 domain to a groove on their prosurvival relatives (Sattler et al. 1997). How the BH3-only and Bcl-2-like proteins control the activation of Bax and Bak, however, remains poorly understood (Adams 2003; Danial and Korsmeyer 2004). Most attention has focused on Bax. This soluble monomeric protein (Hsu et al. 1997; Wolter et al. 1997) normally has its membrane-targeting domain inserted into its groove, probably accounting for its cytosolic localization (Suzuki et al. 2000; Schinzel et al. 2004). Several unrelated peptides/proteins have been proposed to modulate Bax activity (for review, see Lucken-Ardjomande and Martinou 2005), but their physiological relevance remains to be established. Alternatively, Bax may be activated via direct engagement by certain BH3-only proteins, the best documented being the active truncated form of Bid, tBid (Wei et al. 2000; Kuwana et al. 2002; Roucou et al. 2002). As discussed elsewhere (Adams 2003), the oldest model, in which Bcl-2 directly engages Bax (Oltvai et al. 1993), has become problematic because Bcl-2 is membrane bound while Bax is cytosolic, and their interaction seems highly dependent on certain detergents used for cell lysis (Hsu and Youle 1997). Nevertheless, it is well established that the BH3 region of Bax can mediate association with Bcl-2 (Zha and Reed 1997; Wang et al. 1998) and that Bcl-2 prevents the oligomerization of Bax, even though no heterodimers can be detected (Mikhailov et al. 2001). Thus, whether the prosurvival proteins restrain Bax activation directly or indirectly remains uncertain (see Discussion). Although Bax and Bak seem in most circumstances to be functionally equivalent (Lindsten et al. 2000; Wei et al. 2001), substantial differences in their regulation would be expected from their distinct localization in healthy cells. Unlike Bax, which is largely cytosolic, Bak resides in complexes on the outer membrane of mitochondria and on the endoplasmic reticulum of healthy cells (Wei et al. 2000; Zong et al. 2003). Nevertheless, on receipt of cytotoxic signals, both Bax and Bak change conformation, and Bax translocates to the organellar membranes, where both Bax and Bak then form homo-oligomers that can associate, leading to membrane permeabilization (Hsu et al. 1997; Wolter et al. 1997; Antonsson et al. 2001; Wei et al. 2001; Mikhailov et al. 2003). Since Bak, unlike Bax, is normally located at its site of action, how is it kept in check to prevent inappropriate cell death? We were prompted to investigate Bak regulation by recent evidence that it can form complexes with Mcl-1 (Cuconati et al. 2003) and that Mcl-1 is degraded at an early stage of apoptosis (Cuconati et al. 2003; Nijhawan et al. 2003). Here we report evidence from binding and functional studies that Bak is subject to negative regulation specifically by Mcl-1 and Bcl-xL but not other prosurvival family members. Thus, contrary to expectation, the prototypic guardian Bcl-2 is unable to prevent Bak activation. We show that stimuli from DNA damage drive BH3-only proteins to displace Bak from Mcl-1 and Bcl-xL, allowing Bak to self-associate and trigger apoptosis. We also report that the association of Noxa with Mcl-1 can trigger Mcl-1 degradation. Our demonstration that a subset of prosurvival family members controls Bak may explain the varied phenotypes observed on disruption of the prosurvival genes (Ranger et al. 2001) and has important implications for current efforts to develop drugs that regulate apoptosis by targeting the Bcl-2 family (Cory et al. 2003).

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The biochemistry of apoptosis

Abstract: Apoptosis - the regulated destruction of a cell - is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

The Bcl-2 Protein Family: Arbiters of Cell Survival

Abstract: Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer.