Ubiquitin-proteasome pathway as a primary defender against TRAIL-mediated cell death

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptotic cell death as well as expression of proinflammatory genes such as CXCL8 in malignant human astrocytoma cells. However, the molecular mechanisms that determine the fate of cells are not yet understood. The ubiquitin (Ub)-proteasome pathway regulates a wide range of cellular functions through degradation of various regulatory proteins; given this, we hypothesized that this pathway may play a central role in TRAIL-mediated signaling. We demonstrate here that inhibition of the Ub-proteasome pathway enhanced TRAIL-mediated cell death of human astrocytoma CRT-MG cells within hours by blocking degradation of active caspase-8 and -3. Proteasome inhibitors suppressed TRAIL-mediated activation of NF-B; however, inhibition of the NF-B pathway alone was not sufficient to enhance TRAIL-mediated cell death. Collectively, these results suggest that the Ub-proteasome pathway may play an important role as an antiapoptotic surveillance system by eliminating activated caspases as well as mediating NF-B-dependent signals.Received 30 December 2003; received after revision 9 February 2004; accepted 13 February 2004     

The complexity of parathyroid hormone-related proteinsignalling

Our understanding of the mode of action of parathyroid hormone-related protein (PTHrP) has changed profoundly during the last decade. Most PTHrP activities are mediated by membrane receptors through autocrine/paracrine pathways. However, both endogenous and exogenous PTHrP also appear to have intracrine effects through translocation into the nucleus. The present review proposes unconventional PTHrP signalling, based on novel clues. First, PTHrP binding to its membrane receptor triggers internalization of the whole complex, mediated by beta-arrestin. There is growing evidence that the receptor and arrestin are the effectors of biological responses, rather than the ligand (or in addition to the ligand). Second, the existence of putative PTHrP targets within the cytoplasm is beginning to be supported. Recent findings of interactions between a COOH-terminus of PTHrP and beta-arrestin and between the PTHrP receptor and 14-3-3 proteins represent the starting point for identification of intracellular partners of both the hormone and its receptor.Received 19 June 2003; received after revision 10 July 2003; accepted 21 July 2003     

Administration of the antitumor drug mitoguazone protects normal thymocytes against spontaneous and etoposide-induced apoptosis

The suggestion has been made that polyamines may be involved in the control of cell death, since exceedingly high or low levels induce apoptosis in different cell systems. For a deeper insight into the relationship between apoptosis and polyamine metabolism, we investigated in vitro the effect on rat thymocytes of mitoguazone (MGBG, which inhibits S-adenosylmethionine decarboxylase, i.e. a key enzyme in the polyamine biosynthetic pathway). Thymocytes were selected as an especially suitable model system, since they undergo spontaneous apoptosis in vivo and can be easily induced to apoptose in vitro by etoposide, used here as an apoptogenic agent. MGBG protected thymocytes from both spontaneous and drug-induced apoptosis, and this protective effect was associated with a decrease in polyamine oxidase activity and total polyamine levels.Received 7 July 2004; received after revision 2 September 2004; accepted 9 September 2004     

Differential effects of monastrol in two human cell lines

The kinesin-related protein HsEg5 plays essential roles in mitotic spindle dynamics. Although inhibition of HsEg5 has been suggested as an aid in cancer treatment, the effects of such inhibition on human cells have not been characterized. Here we studied the effects of monastrol, an allosteric HsEg5 inhibitor, on AGS and HT29 cell lines and compared them to those of taxol. While both cell lines were similarly sensitive to taxol, AGS cells were more sensitive to monastrol. The differences in sensitivity were determined by the degree of inhibitory effect on cell proliferation, reversibility of monastrol-induced G2/M arrest, intracellular phenotypes and induction of apoptosis. In both cell lines, monastrol-induced apoptosis was accompanied by mitochondrial membrane depolarization and poly-ADP-ribose polymerase 1 cleavage. In AGS, but not HT29 cells, monastrol-induced apoptosis involved a prominent cleavage of procaspases 8 and 3. While in AGS cells, monastrol induced the formation of symmetric microtubule asters only, in HT29 cells, asymmetric asters were also formed, which may be related to specific HsEg5 functions in HT29 cells.Received 18 February 2004; received after revision 30 May 2004; accepted 16 June 2004     

Galectins in cell growth and apoptosis

Fourteen members of the galectin family, proteins with conserved carbohydrate-recognition domains that bind β-galactoside, have been cloned and more are expected to be discovered in the near future. Many aspects of galectin biology have been thoroughly explored, and functional studies have implicated these proteins in cell growth, differentiation and apoptosis, in addition to cell adhesion, chemoattraction and cell migration. In some cases a galectin can either promote or suppress cell growth, depending on the cell types and doses used. Galectin-3 is the only member known so far to inhibit apoptosis, while galectin-1, -7 and -9 promote this cellular process. Galectins can act either extracellularly or intracellularly to exert effects on cell growth and apoptosis. RID="*" ID="*"Corresponding author.     

The Ras family of GTPases in cancer cell invasion

The ability of tumoral cells to invade surrounding tissues is a prerequisite for metastasis. This is the most life-threatening event of tumor progression, and so research is intensely focused on elucidating the mechanisms responsible for invasion and metastasis. The Ras superfamily of GTPases comprises several subfamilies of small GTP-binding proteins whose functions include the control of proliferation, differentiation, and apoptosis, as well as cytoskeleton organization. The development of metastasis is a multistep process that requires coordinated activation of proliferation, motility, changes in normal cell-to-cell and cell-to-substrate contacts, degradation of extracellular matrix, inhibition of apoptosis, and adaptation to an inappropriate tissue environment. Several members of the Ras superfamily of proteins have been implicated in these processes. The present review summarizes the current knowledge in this field.     

低氢、运动及低氢训练对肝细胞凋亡影响的研究进展

低氧与健康的研究是近年来临床医学、环境医学、航空航天医学和运动医学的研究重点问题之一。从肝细胞凋亡的角度研究运动对肝细胞的影响及其与运动性疲劳之间的关系,对科学制定训练计划等具有重要的意义。低氧训练使机体处于更加缺血和缺氧状态,血液的重新分配,使肝脏出现暂时的缺血,运动强度降低后血液重新回流形成血液再灌注,导致肝损伤,诱导细胞凋亡。细胞凋亡的过低或过高都导致疾病的发生。肝细胞凋亡的异常在急、慢性肝损伤的发病机制中起着重要的作用。就有关低氧、运动及低氧训练对肝细胞凋亡的影响,引起凋亡发生的基因调控及机制进行相关综述。     

Simulating FAS-induced apoptosis by using P systems

In contrast to differential equations, P systems are an unconventional model of computation which takes into consideration the discrete character of the quantity of components and the inherent randomness that exists in biological phenomena. The key feature of P systems is their compartmentalised structure which represents the heterogeneity of the structural organisation of the cells, and where one can take into account the role played by membranes in the functioning of the system, for example signalling at the cell surface, selective uptake of substances from the media, diffusion across different compartments, etc. We show here that P systems can be a reliable tool for Systems Biology and could even outperform in some cases the current simulation techniques based on differential equations. We will also use a strategy based on the well known Gillespie algorithm but running on more than one compartment called Multi-compartmental Gillespie Algorithm.     

细胞凋亡检测方法研究进展

细胞凋亡是生命科学目前的一个研究热点.检测细胞凋亡的方法和技术取得了很大的进步.从早期细胞内某些基因转录表达的变化、代谢生理的变化,到晚期细胞形态的确诊、细胞内代谢物质的转变,从定性、定量到原位定性定量等,都发展了相对成熟的检测技术.根据检测时间的早晚,从形态学、生化特性和分子调控等层次综合分析了检测细胞凋亡的主要方法,并对相关研究进行了展望.     

缺血性脑血管病与神经细胞凋亡的研究进展

叙述了细胞凋亡概念及神经细胞凋亡的基本特征。细胞凋亡是迟发性神经元死亡的基本形式，细胞凋亡在短暂性局灶性脑缺血、短暂性全脑缺血及永久性脑缺血中随缺血时间再灌注时间的不同，细胞凋亡发生部位及时间、范围亦不相同。