High apoptotic activity and low epithelial cell proliferation with underexpression of p21(WAF1/CIP1) and p27Kip1 of mucinous carcinomas of the colorectum: comparison with well-differentiated type

We comparatively assessed 41 mucinous colorectal carcinomas (MUCs) and 620 non-MUC (well-, moderately, and poorly differentiated adenocarcinoma) cases for clinicopathologic findings; and 41 MUCs and 115 randomly selected non-MUCs also were studied for the following: (1) apoptotic activity and Ki-67 immunoreactivity; (2) immunohistochemical expression of p21(WAF1/CIP1), p27Kip1, p53, and bcl-2; and (3) c-Ki-ras mutations. The rates for lymph node involvement and peritoneal dissemination were higher in MUCs than in non-MUCs. Multivariate analysis showed MUCs to have a worse prognosis than well-differentiated adenocarcinomas. The Ki-67 labeling for MUCs was significantly lower than that for non-MUCs, whereas the apoptotic index was significantly higher than for the well-differentiated type. The labeling for p21(WAF1/CIP1) and p27Kip1 was lower in MUCs (2.7% and 35.3%, respectively) than in well-differentiated adenocarcinomas (4.2% and 48.6%, respectively). MUCs can be considered a different tumor from the well-differentiated type, with a poor prognosis owing to frequent lymph node metastasis and peritoneal dissemination, and characterized by high apoptotic and low proliferative activities associated with low p21(WAF1/CIP1) and p27Kip1 expression.     

EXPRESSION OF CYCLIN-DEPENDENT KINASE INHIBITOR p21WAF1/CIP1 IN NON-NEOPLASTIC MUCOSA AND NEOPLASIA OF THE STOMACH: RELATIONSHIP WITH p53 STATUS AND PROLIFERATIVE ACTIVITY

The expression of the p53-inducible cyclin-dependent kinase inhibitor p21^WAF1/CIP1 in non-neoplastic mucosa, adenoma, and adenocarcinoma of the stomach was examined immunohistochemically and its relationship with p53 expression and proliferative activity was analysed. In normal gastric mucosa as well as in intestinal metaplasia the epithelial cells at the surface which showed no proliferative activity expressed p21whereas the cells in the deep area of the glands expressing Ki-67 did not. In the neoplastic lesions, the expression of p21^WAF1/CIP1 was detected in 78 per cent (112/144) of the adenomas and 76 per cent (262/343) of the adenocarcinomas. The incidence of p21^WAF1/CIP1 expression did not differ among histological types of gastric carcinoma. The strong expression of p21^WAF1/CIP1 was more frequently observed in carcinomas invading into submucosa or in cases of stages 2, 3, and 4 than in carcinomas limited to the mucosa or in stage 1 cases. The incidence of strongly positive cases was higher in carcinomas with lymph node metastasis than in those without metastasis. There was no apparent correlation between the expression of p21^WAF1/CIP1 and the abnormal accumulation of p53 or with proliferative activity measured by Ki-67 expression. These findings overall suggest that p21^WAF1/CIP1 might be associated with the senescence of non-neoplastic gastric epithelial cells; that a p53-independent pathway might be substantially involved in the induction of p21^WAF1/CIP1 in gastric neoplasia; and that the proliferative activity of gastric cancer might not be solely dependent on control of the cell cycle by p21^WAF1/CIP1.     

胰腺癌p53上下游基因mdm2、p21WAF/CIP1以及P14ARF蛋白的表达及相互关系

目的 探讨p14ARF、p53、mdm2及p21WAF/CIP1蛋白在胰腺癌组织中的表达、相互关系及意义。方法 选取167例胰腺癌、101例癌旁与13例良性病变组织构建组织芯片(又称组织微阵列),应用免疫组织化学EnVision二步法检测这4种蛋白在胰腺良恶性病变中的表达。结果 p14ARF、p53、mdm12及p21WAF/CIP1在胰腺癌中表达的阳性率分别为35.3％(59/167)、57.5％(96/167)、64.1％(107/167)和39.5％(66/167)。同癌旁组织相比,p53和mdm2表达明显升高(P<0.01),而p14ARF和p21WAF/CIP1的表达明显降低(P<0.05)。p21WAF/CIP1的阳性表达与年龄、神经受累显著相关(P<0.05);p53的阳性表达与肿瘤的分化、淋巴结转移和神经受累均显著相关(P<0.05);mdm2的阳性表达与肿瘤的分化显著相关(P<0.05);p14ARF与年龄和浸润转移显著相关(P<0.05)。四者阳性表达两两之间统计学上具有关联性(P<0.05)。结论 p53和mdm2的过表达以及p14ARF和p21WAF/CIP1的缺失表达可能会导致胰腺癌的形成和进展;4种蛋白主要以p14ARF-p53-mdm2-p21WAF/CIP1通路的方式作用于细胞的转化和肿瘤的形成;联合检测p53和mdm2的表达可用于评定胰腺癌的恶性程度。     

Oxygen induces S-phase growth arrest and increases p53 and p21(WAF1/CIP1) expression in human bronchial smooth-muscle cells.

Hyperoxia increases free radical production, leading to DNA damage. Recent studies indicate that oxygen augments the expression of p53 and p21(WAF1/CIP1), and increases apoptotic labeling of airway epithelial cells. Similar changes in regulatory gene products have not been reported in other pulmonary cells, nor have these changes been investigated in conjunction with alterations in cell-cycle distribution. The present study was conducted to determine whether oxygen alters the expression of p53 and p21(WAF1/CIP1) in human bronchial smooth-muscle cells (BSMC). BSMC placed in room air (RA), 40% O(2), or 95% O(2) were examined for 3 d to determine cell number, thymidine incorporation, cell-cycle distribution, and lactate dehydrogenase release. Apoptosis was assessed through the terminal deoxynucleotidyl transferase-deoxyuridine triphosphate end-nick labeling (TUNEL) technique, and p53 and p21(WAF1/CIP1) protein levels were determined through enzyme-linked immunosorbent assay. Exposure of BSMC to 95% O(2) decreased proliferation and DNA synthesis within 24 h, and was accompanied by an increase in S-phase cells (72 h; RA: 12.9 +/- 4.6%, versus 95% O(2): 34.6 +/- 7.0%; P < 0.01). By comparison, exposure to 40% O(2) resulted in decreased proliferation at 48 h without significant alterations in cell-cycle distribution. Both p53 and p21(WAF1/CIP1) levels were increased by 95% O(2), with maximal differences noted at 24 and 48 h, respectively. All atmospheres showed < 8% cell death and few TUNEL-positive cells. Our results indicate that oxygen-mediated alterations in BSMC proliferation are time- and concentration-dependent. Furthermore, high oxygen levels induce S-phase arrest and increased expression of p53 and p21(WAF1/CIP1). Activation of these genes may prevent replication without inducing apoptosis to allow for the repair of oxidative damage.     

Enhanced epithelial cell turnover associated with p53 accumulation and high p21WAF1/CIP1 expression in ulcerative colitis.

To cast light on accelerated epithelial cell turnover as an important risk factor of dysplasia and carcinoma development in patients with long-standing ulcerative colitis (UC), we examined cell proliferation and cell death, as well as expression of apoptosis-related markers, including p53 and p21WAF1/CIP1, in a series of cases. Biopsy specimens (n = 176; 84, active phase; 92, remission) were endoscopically obtained from 25 Japanese patients with UC. As controls, 68 biopsy specimens of normal mucosa were also examined from 27 Japanese patients with colon polyps. We counted the numbers of mitoses, apoptotic bodies, Ki-67-immunoreactive cells, and p21WAF1/CIP1-immunoreactive cells per 1000 crypt cells and the numbers of p53-positive cells per crypt. All of the indices in active UC were significantly higher than in either remitting UC cases or normal cases (mean mitotic index = 0.52, 0.28, and 0.15%, respectively; apoptotic index = 5.40, 2.91, and 1.30%, respectively; Ki-67 labeling index = 39.5, 28.3, and 26.8%, respectively; p21WAF1/CIP1 labeling index = 33.6, 20.0, and 19.0%, respectively; p53 labeling index = 0.66, 0.13, 0.13 per crypt, respectively). In addition, the mitotic, apoptotic, and Ki-67 labeling indices were increased in remitting UC of more than 10 years' duration, in comparison with those of less than 10 years' duration or the normal group. Immunostaining of serial sections revealed a small number of crypt cells coexpressing p53 and p21WAF1/CIP1. Increases in both epithelial cell proliferation and cell death, partially associated with p53 accumulation and high p21WAF1/CIP1 expression, are thus characteristic of active phase UC, as well as in remission of long-standing UC. Accelerated epithelial cell turnover caused by chronic inflammation and epithelial damage might predispose the mucosa to DNA damage, resulting in an elevated risk of mutation in line with dysplasia and carcinoma development in patients with UC.     

胃癌组织cyclinE和p21~(WAF1/CIP1)蛋白表达的意义

目的 :探讨cyclinE和p2 1WAF1/CIP1蛋白在胃癌发生发展中的作用及其表达的意义。方法 :采用免疫组化S P法检测正常胃黏膜、萎缩性胃炎伴肠上皮化生、萎缩性胃炎伴不典型增生各 2 0例和 78例胃腺癌组织中cyclinE和 p2 1WAF1/CIP1蛋白表达。结果 :cyclinE蛋白阳性表达在胃癌组高于正常胃黏膜、萎缩性胃炎伴肠上皮化生组 ,而 p2 1WAF1/CIP1蛋白表达则相反 ,差异均有显著性 (P <0 0 5 ) ;cyclinE、p2 1WAF1/CIP1蛋白表达与胃癌细胞分化程度相关 (P <0 0 5 ) ;有肝转移的胃癌组cyclinE阳性表达率高于无肝转移组 (P <0 0 5 ) ;有淋巴结转移组 p2 1WAF1/CIP1蛋白表达率低于无淋巴结转移组 (P <0 0 5 )。结论 :cyclinE蛋白高表达与 p2 1WAF1/CIP1蛋白失表达可能参与胃癌的发生发展过程 ,检测cyclinE和p2 1WAF1/CIP1蛋白作为反映胃癌病理学特点的参考指标可能有一定意义     

High microvascular density is correlated with high VEGF, iNOS and COX-2 expression in penetrating growth-type early gastric carcinomas

AIMS: Early gastric carcinomas have two characteristic growth types, superficial spreading (SUP) and penetrating (PEN). Higher mucosal apoptotic activity and lower p21(WAF1/CIP1) expression and submucosal low proliferative activity have been shown in the former, compared with the latter. In order to cast light on whether angiogenesis contributes to these growth patterns, the present immunohistochemical study was performed with cancer tissues. METHODS AND RESULTS: Of a total of 807 early gastric carcinomas, 30 PEN and 33 SUP type submucosal invasive carcinoma cases were immunohistochemically compared. CD34 positivity, microvascular density (MVD), and expression of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS), but not cyclooxygenase 2 (COX-2) were higher in cancer cells in both mucosal and submucosal layers in PEN than in SUP (P < 0.05). Submucosal MVD in PEN type was greater (P < 0.01) in cases with high than with low Ki67 labelling. Significant correlations were shown between MVD and VEGF, iNOS and COX-2, and VEGF and iNOS expression in the PEN type, but only a weak correlation between iNOS and COX-2 expression was evident with the SUP type. CONCLUSIONS: Increased MVD in PEN type has an intimate causal relationship to angiogenic factors, high VEGF and iNOS expression. The SUP type, in contrast, has characteristics of low angiogenesis.     

Immunoreactivity of p53, Mdm2, p21(WAF1/CIP1) Bcl-2, and Bax in soft tissue sarcomas: correlation with histologic grade.

Tumor growth depends on 2 distinctive pathways: cell proliferation and apoptosis. The p53 pathway is an important regulator of the cell cycle as it triggers growth arrest or leads to apoptosis in response to cellular stress and therefore is commonly targeted during tumorigenesis. Apoptosis is also controlled by the Bcl-2 family, which includes proapoptotic and antiapoptotic proteins. The aim of this study was to investigate the expression of proteins that are involved in the p53 pathway and apoptosis in different types of soft tissue sarcomas and to correlate the expression of these proteins with the histologic grade of sarcoma cases. One hundred fifty-two cases of different types of soft tissue sarcomas were analyzed. The cases consisted of 54 low-grade, 40 intermediate-grade, and 58 high-grade sarcomas. Immunohistochemical stains for p21(WAF1/CIP1), p53, Mdm2, Bcl-2, and Bax proteins were carried out on tissue microarrays. Nuclear reactivity for p53 was detected in 49 cases (32.2%). Overexpression of Mdm2 was found in 18 cases (11.8%) and p21(WAF1/CIP1) immunostaining was seen in 28 tumors (18.4%). p53 and p21(WAF1/CIP1) expression correlated with the tumor grade (low grade, 5.6% and 3.7%; intermediate grade, 22.5% and 20%; high grade, 63.8% and 31%, respectively). Expression of Bax protein was a common finding in soft tissue sarcoma cases. It was detected in 141 cases (92.8%). Bcl-2 was identified in 59 tumors (38.8%) and was more prevalent in high-grade sarcomas (low grade, 25.9%; intermediate grade, 32.5%; high grade, 55.2%). It was concluded that alterations in the p53 pathway and genes that regulate apoptosis are common events in soft tissue sarcomas. The expression of p53, p21(WAF1/CIP1), and Bcl-2 is closely associated with the histologic grade of the tumor, and therefore these proteins may be used as prognostic markers.     

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.     

转录因子Ets-1对P21WAF1/CIP1启动子的影响

目的：研究转录因子Ets-1对P21WAF1/CIP1启动子的调控作用。 方法:应用瞬时转染、荧光素酶活性测定的方法分析Ets-1对P21WAF1/CIP1启动子荧光素酶报告重组体活性的影响。 结果:荧光素酶活性测定发现Ets-1可以上调P21WAF1/CIP1转录。缺乏激活结构域的Ets-1不能激活P21WAF1/CIP1启动子。Ets-1选择性地作用于P21WAF1/CIP1启动子中-1350GGAA-1347 Ets元件，该元件的序列突变可降低基础表达和Ets-1诱导的P21WAF1/CIP1启动子依赖的表达。-1577GGAT-1574元件介导基础表达，但不介导Ets-1激活的P21WAF1/CIP1启动子依赖的表达。 结论:Ets-1通过-1350GGAA-1347元件调控P21WAF1/CIP1启动子转录。     

Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion

Dysadherin is a cancer-associated cell membrane glycoprotein that down-regulates E-cadherin and plays important roles in tumor progression and metastasis. Differentiated-type gastric carcinoma can be classified into 2 histologic subtypes according to the presence of poorly differentiated components: a mixed type (differentiated carcinoma with poorly differentiated components) and a pure type (purely differentiated-type adenocarcinoma). We studied the clinicopathologic features of 318 cases of differentiated-type gastric carcinoma with submucosal invasion and evaluated the immunohistochemical expression of dysadherin and E-cadherin. We also evaluated 46 cases of metastatic lymph nodes. Tumors with combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression had significantly higher proportions of the moderately differentiated type, deeper submucosal invasion, positivity of lymphatic permeation, and positivity of lymph node metastasis than tumors with other combinations of dysadherin and E-cadherin expression (P = .0009, P = .0015, P = .0273, and P = .0187, respectively). Moreover, the frequency of dysadherin-positive (≥50%) expression was higher in the mixed type (60.3%) than in the pure type (12.4%) (P < .0001), whereas the frequency of E-cadherin-negative (<50%) expression was higher in the mixed type (84.5%) than in the pure type (50.5%) (P < .0001). The frequency of dysadherin expression in the metastatic lymph nodes (80.4%) was significantly higher than that in the primary tumors (45.7%) (P = .001). Dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be correlated with the mixed type. Combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be valuable information for predicting aggressive tumor behavior.     

Expression of p21WAF1/CIP1 in colorectal adenomas and adenocarcinomas and its correlation with p53 protein expression

The expression of p53-Inducible cylln-dependent kinase Inhibitor, p21^WAF1/CIP1 in non-neopiastic mucosa, adenoma and adenocarclnoma of the colorectum was examined by immunohistochemistry and western bootting and Its relation with the expression of p53 protein was analyzed. Non-neoplastic epithelial cells at the surface area showing no proitferative activity expressed p21^WAF1/CIP1.The expression of p21^WAF1/CIP1 was lmmunohistochemlcally detected in 55% (206/377 of the adenomas and 66% (190/289) of the adenocarcinomas, respectively. The lncldence of strongly positive cases was significantly higher In the adenocarcinomas (27%) than In the adenomas (18%) ( P< .05). The incidence of cases wtth strong p21^WAF1/CIP1 expression was higher In stages 0,1 and 2 carcinomas than in stages 3 and 4 carcinomas ( P <0.05). A decrease in the incidence of cases with strong expression was detected in carclnomas Invading deeper than muscularis propria. The influence of strongly positive cases was signiflcantly lower in carcinomas with lymph node metastasis than those without metastasls ( P <0.05). The expression of p21 as well as p53 detected by western blotting was compatlble with the results of lmmunohistochemlstry in most cases examined. However, there was no significant correlatlon between the expression of p21^WAF1/CIP1 and the abnormal accumulation of p53. These findlngs overall suggest that: (i) the physiological expression of p21^WAF1/CIP1 may be associated with cellular senescence of colorectal mucosa; (ii) reduced expression of p21^WAF1/CIP1 participate in the progression of colorectal carcinoma; and (iii) p53-Independent paulway may be considerably Involved In the inductions of p21^WAF1/CIP1.     

p21WAF1/CIP1 expression in gestational trophoblastic disease: correlation with clinicopathological parameters, and Ki67 and p53 gene expression.

BACKGROUND: The p21WAF1/CIP1 gene mediates growth arrest by inhibiting G1 cyclin dependent kinases and has been considered as a downstream effector of the tumour suppressor gene p53. AIM: To analyse the role of p21WAF1/CIP1 in gestational trophoblastic disease. METHODS: The immunohistochemical expression of p21WAF1/CIP1 gene was measured in 33 placentas, 28 partial hydatidiform moles, 54 complete hydatidiform moles, and 13 choriocarcinomas in paraffin wax embedded tissue. The results were correlated with p53 (DO7) and Ki67 (MIB1) immunoreactivity as well as clinical progress. RESULTS: p21WAF1/CIP1 immunoreactivity was found predominantly in the nuclei of the syncytiotrophoblasts. p21WAF1/CIP1 protein expression correlated with gestational age in normal placentas (p = 0.0001) but not in hydatidiform moles (p = 0.89). Complete hydatidiform moles and choriocarcinomas had a significantly higher p21WAF1/CIP1 expression compared with normal placentas and partial hydatidiform moles (p < 0.001); there was no difference between placentas and partial hydatidiform moles. No correlation between p21WAF1/CIP1 expression and either the proliferation (Ki67) index (p = 0.34) or p53 protein accumulation (p = 0.68) was demonstrated. There was no significant difference (p > 0.05) in p21WAF1/CIP1 expression between the 17 patients who developed persistent gestational trophoblastic disease and those who did not. CONCLUSIONS: This study suggests that p21WAF1/CIP1 expression in trophoblastic disease may be induced by a p53 independent pathway. The proliferative activity of gestational trophoblastic diseases might not be determined solely by the control of the cell cycle operated by p21WAF1/CIP1. p21WAF1/CIP1 expression is not an accurate prognostic indicator of gestational trophoblastic disease.     

Protein expression status in mucosal and submucosal portions of early gastric cancers and their predictive value for lymph node metastasis

We aimed to find out predictive markers for lymph node (LN) metastasis of early gastric carcinoma (EGC) by separating evaluation of protein expression in mucosa and submucosa considering tumor heterogeneity. We selected 37 pN1–3 EGCs and depth‐ and size‐matched 31 pN0 EGCs as training set and 72 EGCs including 14 pN1–3 EGCs as test set. Protein expression for β‐catenin, E‐cadherin, N‐cadherin, galectin‐3, c‐MET, TrkB, and Ki‐67 was assessed by immunohistochemistry in mucosal (‐m) and submucosal (‐sm) portions of tumor. In the training set, Ki67‐m was higher than in Ki67‐sm (mean ± SD: 82.67 ± 11.99% vs 61.79 ± 22.53%, p < 0.001). Altered E‐cadherin‐sm, high Ki67‐m, and high Ki67‐sm were correlated with LN metastasis (p < 0.05) and Ki67‐sm was independent with lymphatic invasion and desmoplasia (p = 0.015 by multivariate logistic analysis). The test set confirmed Ki67‐sm and E‐cadherin‐sm as predictors of LN metastasis (p < 0.05). Submucosal EGCs with ≥2 predictive factors out of high Ki67‐sm, altered E‐cadherin‐sm, large tumor size (≥3 cm), diffuse type histology, and present lymphatic invasion yielded 100% sensitivity and 90.9% specificity for prediction of LN metastasis in 21 submucosal EGCs of test set. The proliferative activity of tumor in submucosa is suggested to be an independent predictor for LN metastasis in EGC.     

野生型p53基因诱导肝癌细胞凋亡及p21(WAF1/CIP1)蛋白过表达

目的：研究野生型ｐ５３基因对人肝癌细胞系细胞凋亡的作用。方法：通过脂质体转染方法将野生型ｐ５３基因（ｗｔ－ｐ５３）导入ｐ５３缺陷的ＨＣＣ－９２０４细胞系中，并获稳定表达。结果：转染ｗｔ－ｐ５３后细胞生长缓慢，Ｇ１期细胞数量由转基因前的４８．５％增加到７８．０％，并有较多细胞逐渐死亡。电镜观察和ＤＮＡ分析证实细胞死亡方式主要是细胞凋亡。免疫组化结果显示细胞转染ｗｔ－ｐ５３后，ｐ２１ＷＡＦ１／ＣＩＰ１的表达显著增加。结论：提示外源性野生型ｐ５３基因可以抑制肝癌细胞生长，并诱导细胞凋亡，这可能是通过ｐ２１ＷＡＦ１／ＣＩＰ１途径发挥上述作用的     

转录调节因子Ets-1在大鼠血管平滑肌细胞增殖与凋亡中的作用

目的： 研究转录调节因子Ets-1对大鼠血管平滑肌细胞增殖与凋亡的影响及其可能的机制。 方法： 用定量细胞DNA片段的方法观察大鼠血管平滑肌细胞增殖与凋亡。用Western印迹法检测磷酸化视网膜母细胞瘤（RB-P）蛋白表达。 结果： Ets-1抑制大鼠血管平滑肌细胞凋亡。反义P21WAF1/CIP1能够阻断Ets-1的抗凋亡作用，并抑制Ets-1诱导的平滑肌细胞增殖。Ets-1能够上调RB-P蛋白表达，反义P21WAF1/CIP1可以阻断Ets-1诱导的RB-P蛋白表达。 结论： 在大鼠血管平滑肌细胞中，Ets-1通过P21WAF1/CIP1旁路发挥抑制凋亡和促进增殖作用。