外源性碱性成纤维细胞生长因子对吸烟大鼠脑细胞凋亡及p53表达的影响

目的 研究外源性碱性成纤维细胞生长因子(bFGF)对吸烟大鼠脑细胞凋亡及p53表达的影响.方法 将40只大鼠随机分为4组:正常对照组、长期大量吸烟组、短期大量吸烟组、吸烟+bFGF组(吸烟最后15 d经腹腔内注射bFGF).采用线栓大脑中动脉法建立大鼠脑梗死模型.采用脱氧核苷酸末端转移酶介导的dUTP缺口末端标记技术(TUNEL法)及免疫组化法检测细胞凋亡和p53蛋白表达.结果 各吸烟组脑细胞凋亡及p53蛋白表达较对照组明显增加(P＜0.01),凋亡细胞数量和p53蛋白表强度随吸烟时间和剂量增加而增加(P＜0.01).bFGF治疗组大鼠脑细胞凋亡数及p53蛋白表达较单纯吸烟组明显减少(P＜0.01).结论 吸烟可使大鼠脑细胞凋亡及p53蛋白表达增加,p53介导吸烟诱导的细胞凋亡,细胞凋亡及p53蛋白表达强度与吸烟时间及数量相关,bFGF 通过抑制p53表达减少细胞凋亡.     

玉米苞叶对动脉粥样硬化家兔平滑肌细胞凋亡及p53和Fas蛋白表达的影响

目的：探讨玉米苞叶防治动脉粥样硬化（AS）的机制。方法：选用大耳白家兔，复制家兔AS模型，随机分为动脉粥样硬化模型组，玉米苞叶组和正常对照组，成模后给予玉米苞叶煎剂治疗，8w后处死家兔，采用流氏细胞术检测平滑肌细胞的凋亡率以及凋亡相关基因p53和Fas蛋白表达。结果：模型组血管平滑肌细胞的凋亡率明显高于对照组（P＜0．05），p53和Fas蛋白的表达增强（P＜0．05），主动脉壁肉眼观测出现典型斑块。玉米苞叶组平滑肌细胞的凋亡率明显低于模型组（P＜0．05），p53和Fas蛋白表达下调（P＜0．05）；主动脉斑块面积较模型组明显减小，结论：玉米苞叶通过调节p53和Fas蛋白表达而调节AS家兔平滑肌细胞凋亡。     

一氧化氮在阿霉素肾病大鼠发病中的作用和机制

目的探讨一氧化氮(NO)在阿霉素(ADR)肾病病鼠发病中的作用及其机制.方法复制阿霉素肾病模型,分别用L-精氨酸(L-Arg)及N-硝酸-L精氨酸甲基酯(L-NAME)进行干预,用硝酸还原酶法测定肾皮质匀浆NO代谢产物NO2-/NO-3水平来反映NO水平,用末端标记法和免疫组化法分别检测皮质部细胞凋亡和Bcl-2、Bax、c-Myc蛋白表达情况,用原位杂交法测定皮质部细胞p53-mRNA转录水平.结果①ADR组肾皮质匀浆NO2-/NO3-水平明显低于对照组(P＜0.01),皮质部细胞凋亡数、p53-mRNA水平和c-Myc蛋白表达均分别明显高于对照组(P均小于0.01),肾小管细胞Bcl-2蛋白表达明显低于对照组而Bax蛋白表达却明显高于对照组(P均小于0.01).②ADR+L-Arg组肾皮质匀浆NO2-/NO3-水平明显高于ADR组(P＜0.01),皮质部细胞凋亡数、p53-mRNA水平和c-Myc蛋白表达则分别明显低于ADR组(P均小于0.05),肾小管细胞Bcl-2蛋白表达明显高于ADR组而Bax蛋白表达则明显低于ADR组(P均小于0.05).③ADR+L-NAME组肾皮质匀浆NO2/NO-3水平明显低于ADR组(P＜0.01),皮质部细胞凋亡数、p53-mRNA水平和c-Myc蛋白表达均明显高于ADR组(P均小于0.05),肾小管细胞Bcl-2蛋白表达明显低于ADR组而肾小管细胞Bax蛋白表达明显高于ADR组(P均小于0.05).结论ADR能显著降低ADR肾病病鼠肾皮质NO水平,诱导肾皮质细胞凋亡.L-Arg可对抗ADR的上述作用,在一定程度上维持NO水平,减少细胞凋亡;L-NAME增强ADR作用,进一步降低NO水平,增加细胞凋亡.本实验结果提示,NO水平的增减与细胞凋亡相关,NO可能参与细胞凋亡.     

SLE患者PBMCs细胞凋亡及其相关基因Bax、p53、C-myc蛋白表达的临床意义

目的探讨系统性红斑狼疮（SLE）外周血单个核细胞（PBMCs）细胞凋亡及其相关基因Bax、p53、C-myc蛋白表达在SLE发病中的作用及机制。方法应用流式细胞仪（FCM）检测20例活动期SLE患者（SLE组）及20例健康者（对照组）PBMCs细胞凋亡率及凋亡相关基因Bax、p53、C-myc蛋白表达阳性率;免疫比浊法检测血清补体C,水平,并分析SLE组PBMCs细胞凋亡率与C3水平的相关性。结果SLE组PBMCs细胞凋亡率及Bax、p53、C-myc蛋白表达阳性率均显著高于对照组（P均〈0．01）;SLE组血清补体C,水平显著低于对照组,且SLE组PBMCs细胞凋亡率与血清补体C3水平呈高度负相关（P均〈0．01）。结论Bax、p53、C-myc蛋白表达在SLE发病中具有重要作用,可能机制为诱发PBMCs细胞凋亡失衡及反馈性降低血清补体水平。     

脊髓前角神经元损伤对p38MAPK信号系统影响的研究

目的 探讨大鼠脊髓神经元损伤对p38MAPK信号系统的影响及其作用机制.方法 取大鼠脊髓前角神经元,培养细胞分3组：对照组继续正常培养,模型组及干预组用谷氨酸钠诱导神经元损伤,干预组在加入谷氨酸钠的同时加入p38MAPK阻滞剂.24 h后检测细胞中丙二醛（MDA）含量,以激光共聚焦显微镜定量测定细胞中ERK1/2、JNK和p38的活性.用原位凋亡检测法（TUNEL）检测细胞凋亡率.结果 与对照组比较,模型组、干预组MDA含量、ERK1/2和P38活性明显增高（P＜0.05）,模型组细胞凋亡率明显高于对照组、干预组（P＜0.05）,干预组高于对照组（P＞0.05）.结论 p38MAPK信号系统在脊髓神经元氧化应激损伤导致细胞凋亡过程中起重要作用,其阻滞剂能起到抗细胞凋亡的保护作用.     

胶体~(32)P对原代培养大鼠前列腺细胞的内辐射研究

目的 观察不同浓度胶体~(32)P对原代培养大鼠前列腺细胞凋亡的影响.方法 原代培养大鼠前列腺细胞,分为大剂量辐射组、小剂量辐射组和对照组,采用流式细胞术、TUNEL染色和细胞活力测定检测大鼠前列腺细胞在不同辐射剂量下的细胞凋亡变化.结果 小剂量辐射组细胞凋亡率虽然很低,但是高于对照组(P＜0.01),大剂量辐射组细胞凋亡率明显高于小剂量辐射组和对照组(P＜0.01),并可见亚二倍体峰.与对照组比较,小剂量辐射组细胞活力下降(P＜0.05),大剂量辐射组细胞活力则明显下降(P＜0.01).结论 小剂量辐射对大鼠前列腺细胞的致死性损伤作用不大,仅能引起少量细胞凋亡,大剂量辐射可致大量细胞凋亡.     

IGFBPrP1 siRNA诱导的大鼠肝星状细胞凋亡及其机制

目的研究IGFBPrP1 siRNA对大鼠肝星状细胞凋亡的影响,并探讨其可能的机制。方法体外培养大鼠肝星状细胞株（HSC-T6）,分别设立：正常对照组,阴性对照组,IGFBPrP1 siRNA转染组。IGFBPrP1 siRNA转染大鼠肝星状细胞,转染不同时间后,用CCK-8试剂盒检测肝星状细胞增殖的变化,AnnexinV/PI双标法流式细胞术检测肝星状细胞凋亡的变化,免疫细胞化学染色法检测P53及Bcl-2蛋白表达的变化。结果 （1）IGFBPrP1 siRNA转染大鼠肝星状细胞不同时间（24、48、72 h）后,转染组细胞增殖受到抑制且凋亡率明显增高,与正常对照组及阴性对照组相比,差异均有统计学意义（P〈0.01）;（2）IGFBPrP1 siRNA转染大鼠肝星状细胞48 h后,与正常对照组及阴性对照组相比,转染组P53蛋白的表达量显著增高（P〈0.01）;Bcl-2蛋白的表达明显降低（P〈0.01）。结论 IGFBPrP1 siRNA能显著抑制大鼠肝星状细胞增殖且能促进其凋亡;上调P53的表达,下调Bcl-2的表达可能是IGFBPrP1 siRNA诱导大鼠肝星状细胞凋亡的途径之一;推测抑制IGFBPrP1的表达有可能成为治疗肝纤维化的新靶点。     

硒对高氟所致兔血管内皮损伤及动脉硬化影响的病理形态学研究

目的 研究硒对高氟所致兔动脉血管内皮细胞损伤和动脉硬化病理形态学变化的影响作用.方法 20只健康雄性新西兰白兔,体质量(2.0±0.5)kg,按体质量随机分对照组(饮去离子水,饲基础饲料)、加氟组(饮含氟离子100mg/L去离子水,饲基础饲料)、加硒组(饮含硒1 mg/L去离子水,饲基础饲料)、加氟加硒组(饮含氟离子100 mg/L、含硒1 mg/L去离子水,饲基础饲料),每组5只,实验期6个月.于实验第0、3、6个月取血测定血清含氟量和含硒量;实验终末取胸主动脉,观察主动脉病理及超微结构变化.结果实验第3、6个月时,加氟组和加氟加硒组血清氟[(0.589±0.146)、(0.772±0.175)mg/L和(0.502±0.094)、(0.693±0.158)mg/L]显著高于对照组[(0.174±0.002)、(0.208±0.031)mg/L,P均＜0.01];加氟组第6个月血清氟显著高于第3个月(P＜0.05).实验第3、6个月时,加硒组和加氟加硒组血清硒[(0.252±0.022)、(0.319±0.052)mg/L和(0.239±0.016)、(0.294±0.018)mg/L]显著高于对照组[(0.135±0.014)、(0.167±0.019)mg/L,P均＜0.01];加硒组第6个月血清硒显著高于第3个月(P＜0.05).对照组、加氟组、加硒组、加氟加硒组内皮细胞凋亡指数分别为(4.92±1.32)%、(30.30±6.80)%、(6.57±2.14)%和(14.29±2.99)%,氟与硒各自的主效应有统计学意义(F值分别为106.833、20.082,P均＜0.01),高氟与适硒之间存在显著的拮抗作用(F=30.402,P＜0.01).病理观察加氟组主动脉内皮有红细胞及纤维蛋白沉着,细胞走向及结构发生改变,血管受损严重;加氟加硒组减少内皮细胞凋亡,附着的纤维蛋白以及红细胞数量减少,内皮细胞结构基本正常,血管受损程度和范围明显减轻.结论适量硒抑制高氟引起的内皮细胞凋亡,减轻高氟所致主动脉结构破坏,保持内皮细胞的完整性,以此拮抗高氟对血管的损伤和促动脉粥样硬化作用.     

生长激素对大鼠阿霉素心肌病心肌细胞凋亡及P53的影响

目的探讨生长激素(growth hormone,GH)对阿霉素(adriamycin,ADR)心肌病大鼠心肌细胞凋亡的影响及对凋亡相关基因P53蛋白表达的影响.方法30只雄性Wistar大鼠,体重200～250 g,随机分为3组,对照组、ADR组和GH联用ADR组.用原位末端标记法标记凋亡的心肌细胞,用免疫组织化学方法检测P53蛋白的表达.结果与对照组比较,ADR组心肌细胞凋亡指数升高的差异有统计学意义(P＜0.05),GH联用ADR组细胞凋亡指数低于ADR组(P＜0.05),ADR组P53蛋白表达明显高于对照组(P＜0.05)GH联用ADR组P53蛋白表达明显低于ADR组(P＜0.05).结论阿霉素可使大鼠心肌细胞发生凋亡,同时使P53蛋白表达升高.GH干预治疗可减少阿霉素心肌病的心肌细胞凋亡.     

糖尿病大鼠脑缺血再灌注后脑组织细胞凋亡与Bax、Be1-2及p53基因表达

目的观察糖尿病性高血糖大鼠脑缺血再灌注后脑组织细胞凋亡与Bax、Bc1-2和p53表达情况。方法将Wistar大鼠随机分成正常对照组、假手术组、正常血糖脑缺血再灌注组（NIR）和糖尿病性高血糖脑缺血再灌注组（DIR），采用链脲佐菌素腹腔注射制作糖尿病模型、线栓法制作大脑中动脉缺血再灌注模型，应用TUNEL法和免疫组化法分别检测细胞凋亡和Bax、Bc1-2及p53表达。结果与假手术组和正常对照组比较，NIR组凋亡细胞百分率和Bax、Bc1-2、p53表达明显增加（P均〈0.01）；与NIR组比较，DIR组凋亡细胞百分率和Bax、p53表达明显增加，Bc1-2表达明显降低（P均〈0.01）。结论糖尿病性高血糖大鼠脑缺血再灌注后梗死周边区细胞凋亡增加是高血糖加重缺血性脑损伤的机制之一；Bax和p53表达上调、Bc1-2表达下调参与了糖尿病大鼠脑缺血再灌注后细胞凋亡的调控。     

过量氟对大鼠肝细胞内钙水平和肝细胞凋亡的影响

目的 研究在大鼠过量摄氟后体内对肝细胞中游离钙([Ca~(2+)]i)水平和肝细胞凋亡的影响。方法 应用饮水加入氟化钠进行大鼠染毒实验,采用Fura-2/AM荧光指示剂测定慢性氟中毒大鼠肝细胞内[Ca~(2+)]i浓度的变化,同时利用流式细胞术测定肝细胞凋亡率。结果 过量氟可刺激肝细胞内[Ca~(2+)]i浓度增高,常食(高钙饮食)投氟组与常食对照组相比差异显著(P<0.05),偏食低钙投氟组高于低钙对照组,差异显著(P<0.05);肝细胞凋亡率在正常饮食加氟组与对照组相比差异无显著性(P>0.05),低钙饮食加氟组肝细胞凋亡率明显增高,与低钙对照组相比,差异显著(P<0.05);相关分析显示,低钙饮食投氟组肝细胞内[Ca~(2+)]i浓度增高与细胞凋亡率有相关性趋势(r=0.576)。结论(1)过量氟所致的大鼠肝细胞内[Ca~(2+)]i持续增高对肝细胞凋亡有不同程度的影响,可能在氟骨症病理过程中起重要作用;(2)投氟伴随低钙可加重细胞内[Ca~(2+)]i超负荷和细胞凋亡,提示钙营养与氟中毒发病有着重要联系;(3)肝细胞内[Ca~(2+)]i增高与肝细胞凋亡率之间有无相关性有待于进一步研究证实。     

低Se低VE诱导肝细胞凋亡及相关基因所起的作用

目的 研究低硒（Ｓｅ）低维生素Ｅ（ＶＥ）能否诱导大鼠肝细胞凋亡及相关基因ｐ５３、ｂｃｌ－２和ｃ－ｍｙｃ所起的作用。方法 以天然的和人工半合成的低Ｓｅ低ＶＥ饲料喂养大鼠１７周,采用末端脱氧核苷酸转移酶介导的缺口末端标记（ＴＵＮＥＬ）检测肝细胞凋亡,采用免疫组化法检测肝细胞ｐ５３、ｂｃｌ－２和ｃ－ｍｙｃ蛋白。结果 与补Ｓｅ和ＶＥ组大鼠相比,低Ｓｅ低ＶＥ组大鼠肝细胞凋亡显著增加;ｐ５３和ｃ－ｍｙｃ蛋白增     

T cells are depleted in HCV-Induced hepatocellular carcinoma patients: possible role of apoptosis and p53

Egypt has possibly the highest Hepatitis C Virus (HCV) prevalence worldwide. A high proportion of HCV infections become chronic and lead to liver cirrhosis and hepatocellular carcinoma (HCC). The cellular and molecular mechanisms behind HCV infection complication are not completely understood although apoptosis has been implicated in this process. Using flowcytometry, we examined whether T lymphocyte; isolated from patients with HCV and HCV-associated HCC (HCV-HCC); are predestined in vivo to undergo spontaneous apoptosis. Also, the role of p53; a key protein in apoptotic process; in the development of HCC was examined. Our data showed that T cells were severely depleted in HCV-HCC patients and its spontaneous apoptosis was higher in patient groups as compared to normal controls. In addition, p53 expression in liver tissue (determined by ELISA) was higher in the HCC patient groups as compared to normal controls and correlated well with the HCC grade. In conclusion, HCV infection induces peripheral T cell apoptosis, depletion and subsequently immune-suppression and this may lead to persistence of infection. Also, p53 is implicated in the poor prognosis of HCV-HCC and could be used as a predictive marker to assess the prognosis of HCC patients.     

慢性氟中毒大鼠神经细胞凋亡的研究

目的 研究慢性氟中毒对神经细胞的作用机制,特别是氟中毒与细胞凋亡的关系。方法 采用末端标记法和流式细胞仪观察法,测定了慢性氟中毒鼠脑组织中神经细胞的凋亡情况。结果 ＴＵＮＥＬ检测显示,在大鼠慢性氟中毒模型中,可见到明显的ＤＡＢ着染的阳性凋亡细胞,而且这种表达具有选择性,仅出现在海马ＣＡ４区。流式细胞仪显示,正常脑组织中的神经细胞即可测得凋亡峰;慢性氟中毒组脑组织中的凋亡峰明显高于正常对照组,但不同     

Placental apoptosis in recurrent miscarriage

Apoptosis is an interactive and dynamic biological process involved in all phases of embryogenesis. We aimed to study the effect of placental apoptosis on recurrent miscarriage (RM). Placental tissue samples were collected from 40 women with RM (study group) and 30 women with sporadic spontaneous abortion (control group). Samples were prepared and stained immunohistochemically with markers for both the apoptotic protein (p53) and anti-apoptotic Bcl-2 antibodies. Our results showed that expression of the apoptotic (p53) protein was significantly increased in the placental tissues of the RM group (p = 0.003). By contrast, the expression of anti-apoptotic (Bcl-2) antibodies was significantly increased in the placental tissues of the control group (p = 0.025). We concluded that placental apoptosis plays a crucial role in pregnancy continuation. However, increased p53 expression in placental tissue in early pregnancy could negatively affect pregnancy continuation.     

Contributions of p53 and PMA to g-irradiation induced apoptosis in Jurkat cells

Several mutations prevent the expression of p53 in the human lymphoblastoid T cell line Jurkat. Restoration of p53 in Jurkat cells had no effect on the cell growth but markedly increased the amount of apoptosis induced by g-irradiation. Inhibition of RNA synthesis using 5,6-dichlorobenimidizole riboside had little effect on apoptosis induced by irradiation in the presence of p53 and did not affect the p53-independent apoptotic pathway. Expression of p53 also had no effect on the expression levels of proteins such as Fas, GADD45, Bax, Bcl-2, Bcl-x_L or p53 induced proteins (PIGS) in resting cells or after irradiation. Activation of protein kinase C by phorbol 12-myristate 13-acetate produced an almost complete inhibition of p53-independent apoptosis following irradiation, whereas no significant effect was observed on the rate of p53-induced apoptosis. Although phorbol 12-myristate 13-acetate strongly induced p21 and stabilised p53 in the resting transfected Jurkat cells, neither apoptosis nor cell arrest was observed. In summary, this work shows that p53 enhances the radiosensitivity of Jurkat cells through an apoptotic process that is triggered by irradiation and is largely independent of RNA synthesis and protein kinase C activation. Apoptosis in p53- negative Jurkat cells is strongly inhibited by PMA indicating that the pathway triggered by p53 may be distinct from apoptotic pathways used in its absence.     

PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice

Hepatocyte death and proliferation contribute to hepatocellular carcinoma development after carcinogen exposure or chronic liver inflammation. However, the role and the molecular targets of hepatocyte death in relation to compensatory proliferation have not been fully characterized. In this study, we investigated the role of p53 up-regulated modulator of apoptosis (PUMA), a BH3-only protein important for both p53-dependent and -independent apoptosis, in a diethylnitrosamine (DEN)-induced liver carcinogenesis model. PUMA deficiency significantly decreased the multiplicity and size of liver tumors. DEN treatment induced p53-independent PUMA expression, PUMA-dependent hepatocyte death, and compensatory proliferation. Furthermore, inhibition or deletion of c-jun N-terminal kinase 1 (JNK1) abrogated PUMA induction, hepatocyte death, and compensatory proliferation. CONCLUSION: These results provide direct evidence that JNK1/PUMA-dependent apoptosis promotes chemical hepatocarcinogenesis through compensatory proliferation, and suggest apoptotic inducers as potential therapeutic targets in liver injury and cancer.     

Mutant p53 expression and apoptotic activity of Helicobacter pylori positive and negative gastritis in correlation with the presence of intestinal metaplasia

BACKGROUND: Mutation of the p53 gene is detectable in most cases of gastric cancer, as it is the most common genetic alteration in human malignancies. It is also well documented that Helicobacter pylori infection plays an important role in gastric carcinogenesis. There is still no clarification, however, concerning how genetic instability influences the homeostasis of gastric epithelium. We have studied the effect of H. pylori infection on apoptosis of the antral epithelium in the presence/absence of intestinal metaplasia and the expression of the p53 oncoprotein. The relationship between these two processes is analysed. METHODS: Antral biopsies were taken from 36 patients who underwent routine upper endoscopy (17 men, 19 women, mean age 61.0 years). The biopsies were fixed in formalin and embedded in paraffin. Patients were classified into two histological groups: (1) as chronic gastritis without intestinal metaplasia (n = 19), and (2) chronic gastritis with intestinal metaplasia (n = 17). An immunohistochemical method was used to detect the expression of p53 oncoprotein, and the terminal transferase mediated dUTP nick end-labelling (TUNEL) method was used to detect apoptotic cells. RESULTS: In the absence of intestinal metaplasia, both the apoptotic index (0.0272 +/- 0.011 vs 0.0128 +/- 0.006) and expresssion of p53 (35.55 +/- 31.16 vs 18.33 +/- 19.65) were significantly higher in H. pylori positive cases compared to H. pylori negative cases. In the presence of intestinal metaplasia, p53 expression was further increased (P < 0.05), but apoptosis was similar to that observed in H. pylori negative gastritis without intestinal metaplasia. In the presence of intestinal metaplasia, H. pylori infection did not influence apoptosis (0.013 +/- 0.004 vs 0.011 +/- 0.004), or p53 ratio (70.16 +/- 22.54 vs 68.50 +/- 28.96). In the sequence of gastritis-intestinal metaplasia the two indices show a close negative correlation (P < 0.05). CONCLUSION: In the absence of intestinal metaplasia H. pylori infection increases both apoptotic activity and expression of p53 oncoprotein in the gastric mucosa. The lack of increased apoptosis with a higher p53 expression in the presence of intestinal metaplasia suggests an increased genetic instability and also may suggest that mutation of the p53 gene is an early step in the multistep process of gastric carcinogenesis.     

Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes

We recently reported increased sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Here, we show that only specific-not nonspecific-proteasomal inhibitors can discriminate between malignant and normal lymphocytes in inducing the apoptotic death response. Indeed, lactacystin and its active metabolite clasto-lactacystin beta-lactone induced apoptotic death in CLL but not in normal lymphocytes. This difference was completely abolished when tripeptide aldehydes such as MG132 or LLnL (which can also inhibit calpains) were used as less specific proteasomal inhibitors. Moreover, B-CLL cells exhibited a constitutive altered ubiquitin-proteasome system, including a threefold higher chymotrypsin-like proteasomal activity and high levels of nuclear ubiquitin-conjugated proteins compared with normal lymphocytes. Interestingly, B-CLL cells also displayed altered proteolytic regulation of wild-type p53, an apoptotic factor reported to be a substrate for the ubiquitin-proteasome system. Nuclear wild-type p53 accumulated after lactacystin treatment used at the discriminating concentration in malignant, but not in normal, lymphocytes. In contrast, p53 was stabilized by MG132 or LLnL in malignant and normal cells undergoing apoptosis, indicating that in normal lymphocytes p53 is regulated mainly by calpains and not by the ubiquitin-proteasome system. This work raises the possibility that two different proteolytic pathways controlling p53 stability may be pathologically imbalanced. This could result in modification of apoptosis control, since in CLL-lymphocytes a highly upregulated ubiquitin-proteasome system, which controls p53 stability among other apoptotic factors, was correlated with an increased propensity of these cells to apoptosis triggered by lactacystin.