Abnormal expression of bcl-2 and bax in rat tongue mucosa during the development of squamous cell carcinoma induced by 4-nitroquinoline 1-oxide

4-Nitroquinoline 1-oxide (4NQO)-induced rat tongue carcinogenesis is a useful model for studying oral squamous cell carcinoma. The aim of this study was to investigate the expression of bcl-2 and bax during tongue carcinogenesis induced by 4NQO. Male Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO solution through their drinking water for 4, 12 or 20 weeks. Ten animals were used as negative control. Although no histological changes were induced in the epithelium after 4 weeks of carcinogen exposure, bcl-2 and bax were over-expressed (P < 0.01) in all layers of the 'normal' epithelium. The expression levels were the same in all layers of epithelium for both the antibodies used (bcl-2 or bax). In dysplastic lesions at 12 weeks following carcinogen administration, the levels of bcl-2 and bax expression did not increase when compared to negative control with the immunoreactivity for bcl-2 being restricted to the superficial layer of epithelium. In well-differentiated squamous cell carcinoma induced after 20 weeks of treatment with 4NQO, bcl-2 was expressed in some cells of tumour islands. On the other hand, immunostaining for bax was widely observed at the tumour nests. The labelling index for bcl-2 and bax showed an increase (P < 0.05) after only 4 weeks of 4NQO administration. In conclusion, our results suggest that abnormalities in the apoptosis pathways are associated with the development of persistent clones of mutated-epithelial cells in the oral mucosa. Bcl-2 and bax expression appears to be associated with a risk factor in the progression of oral cancer.     

不同胎龄的胎儿和少儿皮肤中bax,bcl-2和p53基因表达的变化

目的：探讨凋亡相关基因bax, bcl-2和p53在不同胎龄的胎儿皮肤和少儿皮肤组织中表达的变化特征及其可能的生物学意义。方法： 运用末端脱氧核糖转移酶介导的生物素化脱氧尿嘧啶缺口标记技术(TUNEL)检测18例不同胎龄(13-32周)的胎儿皮肤和6例少儿皮肤组织中细胞凋亡的变化后，提取这些皮肤组织中的总RNA，分离mRNA，用RT-PCR方法检测bax, bcl-2和p53基因在不同组织中的表达变化特征。结果： 随着胎儿的生长发育，皮肤组织中的细胞凋亡率逐渐增加。在早期妊娠胎儿的皮肤中，bcl-2基因表达水平较高，随着胎龄的增加，bcl-2基因的转录本含量逐渐降低，在少儿的皮肤组织中，这种基因的表达量明显低于早期妊娠胎儿皮肤（P<0.01）。与bcl-2基因不同，在早期妊娠胎儿皮肤组织中，p53基因表达水平较低，而在晚期妊娠胎儿和少儿的皮肤内，该基因表达较强，而bax基因在不同发育时期的胎儿和少儿皮肤组织中表达差异不显著（P>0.05）。结论： 晚期妊娠胎儿和少儿皮肤组织中细胞增殖减缓，细胞趋向分化或凋亡的增加可能与p53基因表达增强，bcl-2表达降低相关；而p53表达降低，bcl-2表达升高可能是早期妊娠胎儿皮肤中细胞凋亡较少的机制之一。     

Correlation between proliferative processes and cell death in non-small cell lung cancer with glandular differentiation at different stages of tumor progression

Surgical material (removed lungs or their parts) from 58 patients operated in 1993-1998 was investigated. Lung adenocarcinomas (LAC) are characterized by low proliferative activity of tumor cells. With a decrease of LAC differentiation, tumor cell death by terminal differentiation also diminished which was accompanied by low bcl-2 expression and enhancement of spontaneous apoptosis with active accumulation of protein products of p53 expression in tumor cells nuclei. Expression of c-myc and bax remained unchanged. On the whole, the picture reminds that in lung squamous cell carcinoma. Bronchioloalveolar carcinoma is characterized by low proliferative activity combined with higher apoptosis compared to LAC. Large cell lung carcinoma and adenomatous-squamous lung carcinoma demonstrated the highest proliferation and spontaneous apoptosis of tumor cells with accumulation in these cells of p53, bcl-2 and bax comparing to non-small cell lung carcinoma (NSLC) with adenomatous differentiation. Progression of NCLC with adenomatous differentiation largely depends not only on proliferative activity of tumor cells but on tumor cell death due to terminal differentiation, apoptosis and necrosis as well.     

浅蓝菌素对人结肠癌细胞LoVo在裸鼠体内生长的抑制作用

目的 研究脂肪酸合酶抑制剂－浅蓝菌素对人结肠癌细胞ＬｏＶｏ在裸鼠体内生长的抑制作用。方法 建立人结肠癌裸鼠移植瘤模型,浅蓝菌素每次８０ｍｇ／ｋｇ体重、１６０ｍｇ／ｋｇ体重腹腔注射１０次,动态观察肿瘤体积及抑瘤率,治疗后１７ｄ处死并解剖动物,瘤组织做形态学观察和免疫组织化学ＳＰ法检测。结果 不同浓度浅蓝菌素处理人结肠癌细胞ＬｏＶｏ裸鼠移植瘤模型,低剂量和高剂量浅蓝菌素的体积抑瘤率分别为３７．７％和６３．８％,后者接近常规化疗药物５－Ｆｕ治疗对照组（６５．８％）。瘤体组织学显示为人未分化结肠腺瘤,浅蓝菌素处理的移植瘤组织内瘤细胞出现明显的细胞凋亡的超微结构改变,免疫组织化学显示ｂｃ１－２蛋白表达率低于对照组,ｂａｘ基因蛋白的表达结果则相反。结论 浅蓝菌素能够选择性地抑制人结肠癌细胞ＬｏＶｏ细胞在裸鼠体内的生长,这种     

Bax/bcl-2: cellular modulator of apoptosis in feline skin and basal cell tumours

Bcl-2 and bax are two members of the BCL-2 gene family that play a prominent role in the regulation of apoptosis. Bax and bcl-2 expression were examined immunohistochemically in normal (healthy) feline skin and in 24 benign feline cutaneous basal cell tumours. The tumours were also examined for cellular proliferation by measurement of reactivity for the proliferation marker Ki-67, and for apoptosis by in-situ labelling for fragmented DNA. Bcl-2 was detected in normal basal epithelium and in 23 of 24 basal cell tumours. Bax was detected in both basal and suprabasal epithelium, but in only seven of 24 tumours. For tumours that expressed both bax and bcl-2, the bax:bcl-2 ratio was low. Neither bax nor bcl-2 expression was detected in 14 feline cutaneous squamous cell carcinomas. Basal cell tumours showed modest cellular proliferation (median, 17.5% Ki-67- reactive cells), but few (less than 1%) apoptotic cells. The slow, indolent growth of feline cutaneous basal cells in these benign skin tumours may be a response, at least in part, to opposing regulatory expressions of bcl-2 and bax. Copyright Harcourt Publishers Ltd.     

人参皂苷Rg1对缺氧复氧BMSCs增殖和凋亡的影响

目的　探讨人参皂苷Rg1(ginsenoside Rg1)对缺氧复氧BMSCs增殖和凋亡的影响,并探讨其可能机制。 方法　实验分为BMSCs正常对照组、BMSCs缺氧复氧组(Model组)、人参皂苷Rg1 1×10-7、1×10-6 、1×10-5 mol/L处理组、尼莫地平2.5×10-7 mol/L处理组（阳性对照组）。各组分别于缺氧复氧12h前加入完全培养基（正常对照组、Model组）、人参皂苷Rg1（人参皂苷Rg1各处理组）、尼莫地平（阳性对照组）。建立缺氧复氧BMSCs模型。采用TUNEL法检测各组的细胞凋亡率,免疫荧光和免疫印迹技术定性定量检测各组增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)、Bcl-2、Bax的表达情况。 结果 TUNEL结果显示,BMSCs正常对照组未见明显凋亡细胞,Model组可见明显的凋亡细胞,与Model组比较,其余各处理组凋亡细胞数量均减少,以人参皂苷Rg1（1×10-5mol/L）组最为明显。免疫荧光和免疫印迹结果显示,BMSCs正常对照组可见少量的PCNA 、bcl-2、bax表达;Model组的PCNA 、bcl-2的表达减少,但bax的表达显著增高,bcl-2/bax比值降低;与Model组比较,人参皂苷Rg1各组PCNA 、bcl-2表达均呈不同程度的增高,而bax表达呈现相反的趋势,bcl-2/bax比值增高,以Rg1 (1×10-5 mol/L)组最为明显。 结论 人参皂苷Rg1预处理对缺氧复氧BMSCs具有保护作用,其机制可能与下调bax的表达,上调PCNA 、bcl-2的表达,抑制BMSCs凋亡和促进BMSCs增殖有关。     

De novo programmed cell death in oral cancer

AIM: The importance of programmed cell death or apoptosis in the maintenance of tissue homoeostasis and the pathogenesis of oral cancer was analysed in relation to apoptosis regulatory proteins, tissue proliferation and tumour histology. METHODS AND RESULTS: The extent of apoptosis was defined by morphological criteria and the TUNEL (terminal deoxy nucleotidyl transferase-mediated dUTP biotin nick end labelling) assay. p53, bax, bcl-2 and cyclin D1 expression was evaluated by immunocytochemistry. The presence of mutant p53 was analysed using a mutant p53-specific ELISA. An inverse correlation was observed between TUNEL reactivity and histology of the lesion (r = -0.555, P = 0.0001). There was also correlation between TUNEL reactivity and immunoreactivity of apoptosis regulatory proteins. p53 (r = 0.641, P = 0.00023), bcl-2 (r = -0.642, P = 0.00014) and bax (r = 0.651, P = 0.00002). The presence of mutant p53 protein showed an inverse correlation to the extent of apoptosis (r = - 0.301, P = 0.00063). Significant correlation was evident between the bax/bcl-2 ratio and TUNEL (r = 0.652, P = 0.00001) as well as between cyclin D1 and TUNEL reactivity (r = 0.577, P = 0.00001). CONCLUSIONS: Results from this study suggest that apoptosis decreases as histological abnormality increases. Apoptotic regulatory proteins are also altered in a histologically dependent manner. Deregulated proliferation occurs simultaneously with decreased apoptosis during tumour progression in the oral mucosa.     

Regulation of proliferation and apoptosis in sporadic and hereditary medullary thyroid carcinomas and their putative precursor lesions

C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) in patients affected by germline mutations of the RET oncogene represent an exceptional opportunity to study the regulation of proliferation and apoptosis during tumour initiation and progression. In 56 specimens [CCH, n=1; MTC with CCH, n=26; MTC, n=20; lymph-node metastasis (LNM), n=9] from 46 patients [multiple endocrine neoplasia type 2a (MEN2a), n=24; MEN2b, n=2; familiar MTC (FMTC), n=4; sporadic MTC, n=16] and 3 cases of non-neoplastic CCH, proliferation activity (MIB1), the rate of apoptosis [dUTP nick end labelling (TUNEL)] and expression of p53, bcl-2, bcl-x and bax were investigated and compared with clinical data. In MEN-associated CCH and small MTC, bcl-2 was strongly expressed, bcl-x was moderately expressed and bax was only weakly expressed. Advanced tumours and LNM did show a more heterogeneous bcl-2 staining accompanied by an increased bax expression and accelerated proliferation. The rate of apoptosis was extremely low in all investigated tumours. P53 was detectable in three patients with rapidly growing and extensively metastasising MTC. No somatic p53 mutations were found. Hereditary MTC with germline RET mutations at codon 918 (MEN2b) and codon 634 revealed a bias towards a higher proliferation activity at a younger age and are more frequently accompanied by LNM. CCH and MTC are characterised with a preponderance of bcl-2 as a factor blocking the programmed cell death. While MTC, in general, is a slowly growing tumour, a minority of tumours do progress rapidly with high proliferation. The factors leading to an accelerated tumour progression do not seem to take their effect via the regulation of apoptosis. Certain alterations of RET are supposed to have a direct or indirect implication on proliferation and, because of this, an effect on the clinical course. Received: 10 January 2000 / Accepted: 1 March 2000     

Inhibition of 4-nitroquinoline-1-oxide-induced oral carcinogenesis by dietary calcium

Calcium is a strong inducer of keratinocyte differentiation. We have previously demonstrated that extracellular calcium promotes keratinocyte differentiation via E-cadherin-catenin complex-mediated phospholipase C-γ1 (PLC-γ1) activation in the plasma membrane. However, it is unclear whether dietary calcium regulates keratinocyte proliferation, differentiation or carcinogenesis. To address this issue, the rates of oral tumor and levels of proliferation and differentiation in the oral epithelium were assessed in mice on different calcium diets and the carcinogen 4-nitroquinoline-1-oxide. The results showed that mice on the high calcium diet had lower rates of oral tumors, lower levels of proliferation and higher levels of differentiation in the normal oral epithelium than those on the normal calcium diet. Higher levels of E-cadherin, β-catenin, p120-catenin (p120), epidermal growth factor receptor (EGFR), and calcium and lower levels of PLC-γ1 were also noted in the normal oral epithelium in mice on high calcium diet than the control mice. In contrast, mice on low calcium diet had opposite effects. However, dietary calcium had no effect on the proliferation, differentiation or the levels of E-cadherin, β-catenin, p120, PLC-γ1 and EGFR in oral tumors. These data indicate that dietary calcium increases calcium levels in oral epithelium, suppresses oral carcinogenesis, inhibits proliferation and promotes differentiation of normal oral epithelium. Increased E-cadherin, β-catenin, p120 and EGFR and decreased PLC-γ1 may participate in the inhibitory effect of dietary calcium in oral carcinogenesis.     

Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas

Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases. Received: 22 June 1999 / Accepted: 24 September 1999     

Critical roles of PPARβ/δ in keratinocyte response to inflammation

The immediate response to skin injury is the release of inflammatory signals. It is shown here, by use of cultures of primary keratinocytes from wild-type and PPAR beta/delta(-/-) mice, that such signals including TNF-alpha and IFN-gamma, induce keratinocyte differentiation. This cytokine-dependent cell differentiation pathway requires up-regulation of the PPAR beta/delta gene via the stress-associated kinase cascade, which targets an AP-1 site in the PPAR beta/delta promoter. In addition, the pro-inflammatory cytokines also initiate the production of endogenous PPAR beta/delta ligands, which are essential for PPAR beta/delta activation and action. Activated PPAR beta/delta regulates the expression of genes associated with apoptosis resulting in an increased resistance of cultured keratinocytes to cell death. This effect is also observed in vivo during wound healing after an injury, as shown in dorsal skin of PPAR beta/delta(+/+) and PPAR beta/delta(+/-) mice.     

IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma

AIMS: To characterize the expression pattern of IL-6 and its receptors (IL-6R(alpha) and gp130), to relate this pattern to bcl-2 and bax expression and to elucidate the effects on the proliferation/apoptosis equilibrium in benign conditions and in situ and infiltrating breast cancer. METHODS AND RESULTS: The immunoexpression of IL-6 and its receptors (IL-6R(alpha) and gp130), and their relationship with bcl-2 and bax proteins, were studied in in situ and infiltrating tumours and in benign breast lesions by means of Western blotting and immunohistochemistry. The percentages of samples positive for IL-6, bcl-2 and bax and their immunoreaction densities were higher in in situ carcinomas and infiltrating tumours than in benign lesions; although in in situ lesions were not so high as in infiltrating tumours, except for bax, whose immunoexpression was as weak as in benign conditions, resulting in a bcl-2/bax ratio higher than in infiltrating tumours. CONCLUSIONS: The high expression of IL-6 and its receptors in tumours might be related to the enhanced cell proliferation occurring in breast cancer. IL-6 could act by increasing bcl-2 expression and thus altering the proliferation/apoptosis balance toward neoplastic cell proliferation. The increased bax immunoreactivity observed only in infiltrating tumours, which was not so high as the increase in bcl-2 immunoreactivity, might be interpreted as an attempt to hinder cell proliferation.     

Programmed cell death in the regenerating deer antler

Antlers are the only mammalian appendages capable of epimorphic regeneration and thus provide a unique model for investigating the mechanisms that underlie mammalian regeneration. Antlers elongate by a modified endochondral ossification process while intramembranous ossification takes place concurrently around the antler shaft. In this study, sites of apoptosis in the growing antler tip were identified by TUNEL staining and related to cell proliferation, as determined by PCNA staining. Bcl-2 and bax were identified by RT-PCR and bax was also immunolocalized in tissue sections. The apoptotic index was high in perichondrium, undifferentiated mesenchymal cells and cellular periosteum but was low in skin. The proliferation index was high in mesenchyme, skin (specifically in hair follicles) and cellular periosteum; it was low in fibrous perichondrium and periosteum, and barely detectable in cartilage. Both bcl-2 and bax were found to be more highly expressed in the perichondrium/mesenchyme and non-mineralized cartilage than in skin and mineralized cartilage. Bax was immunolocalized in mesenchyme cells, chondroprogenitors, chondrocytes, osteoblasts, osteocytes and osteoclasts. In conclusion, this study shows that programmed cell death plays a necessary role in regenerating antlers, as it does during skeletal development, bone growth and bone remodelling. The high level of apoptosis and proliferation in mesenchymal progenitor cells confirms that this represents the antler 'growth zone'. In fact, the percentage of TUNEL-positive cells in the mesenchymal growth zone (up to 64%) is higher than that recorded in any other adult tissue. This extensive cell death probably reflects the phenomenal rate of morphogenesis and tissue remodelling that takes place in a growing antler. The local and/or systemic factors that control the balance between cell growth and apoptosis in antler tissues now need to be determined.     

Oral squamous cell carcinoma is associated with decreased bcl-2/bax expression ratio and increased apoptosis.

Expression of bcl-2 and bax and apoptosis were studied in fresh frozen samples of normal oral epithelium (OE, n = 7) and oral squamous cell carcinomas (OSCC, n = 16) by immunohistochemistry and the TUNEL method. In OE, bcl-2 was expressed in both basal (96.6% +/- 2.3% [mean +/- SD]) and suprabasal (91.8% +/- 6.2%) compartments. In OSCC, compared with OE, there was a marked reduction of bcl-2-positive cells in the basal part, and in the central parts of well-differentiated (33.0% +/- 19.7%, P < .001) and moderately differentiated (6.1% +/- 4.6%, P < .001) and also in poorly differentiated (1.9% +/- 0.2%, P < .001) tumors. More cells expressed bax in the suprabasal layer of OE (65.6% +/- 9.9%) and central parts of OSCC than in the basal layer of OE (19.1% +/- 4.1%) and basal parts of OSCC. A higher proportion of cells expressed bax in the central part of well-differentiated OSCC (74.3% +/- 8.2%) than in poorly differentiated OSCC (24.9% +/- 9.7%, P < .001). Apoptotic cell death was more pronounced in OSCC (1.5% +/- 0.9%) than in OE (0.4% +/- 0.1%, P < .05). We conclude that, in OSCC, compared with OE, there is a decreased bcl-2 expression, a lowered bcl-2/bax ratio and increased apoptosis. The expression of bax correlates with histological tumor grading in oral squamous cell carcinoma.     

Survivin、Bcl-2和Bax蛋白在乳腺癌中的表达及其意义

目的：检测乳腺癌中 Survivin、Bc(?)-2和 Bax 蛋白的表达,探讨它们的相关性及临床意义。方法：用免疫组化和图像分析技术对乳腺癌中3种蛋白的表达进行定性、定位和定量研究。结果：(1)Survivin 在乳腺癌中表达, 并与临床分期有关;在正常乳腺组织中不表达,两者比较有显著性差异;(2)Bc(?)-2在乳腺癌中表达高于正常乳腺组织。Bc(?)-2与乳腺癌病理分级、临床分期有关;(3)Bax 在乳腺癌中表达低于正常乳腺组织。Bax 与乳腺癌病理分级、临床分期及腋淋巴结转移有关;(4)乳腺癌中 Survivin 的表达与 Bc(?)-2表达正相关,与 Bax 表达无关。结论：3种蛋白可通过抑制或促进细胞凋亡,对乳腺癌发生和发展起重要作用;在乳腺癌发展中 Survivin 与 Bc(?)-2 起协同作用。     

Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages

Inflammation contributes to tumour growth, invasion and angiogenesis. We investigated the contribution of macrophages and their polarization to tumour progression in a model of VEGF-A-induced skin carcinogenesis. Transfection of the human non-tumourigenic keratinocyte cell line HaCaT with murine VEGF-A leads to malignant tumour growth in vivo. The resulting tumours are characterized by extensive vascularization, invasive growth and high numbers of M2-polarized macrophages that crucially contribute to the establishment of the malignant phenotype. Accordingly, macrophage depletion from tumour-bearing animals resulted in reduced tumour growth, inhibition of invasion, decreased proliferation and reduced angiogenesis. In vitro, VEGF-A exerted a chemo-attracting effect on macrophages, but did not induce M2 polarization. We identified IL-4 and IL-10 as the factors involved in M2 polarization. These factors were produced by tumour cells (IL-10) and macrophages (IL-4) in vivo. Addition of recombinant IL-4 and IL-10 in vitro induced a pro-invasive M2 macrophage phenotype and inhibition of the IL-4 receptor in vivo blocked M2 polarization of macrophages, resulting in a less aggressive tumour phenotype. Thus, we provide evidence that M2 macrophages are crucial for the development of VEGF-A-induced skin tumours and that VEGF-A contributes to malignant tumour growth, not only by enhancing angiogenesis but also by establishing an anti-inflammatory microenvironment. However, VEGF-A alone is not sufficient to create a tumour-promoting microenvironment and requires the presence of IL-4 and IL-10 to induce M2 polarization of macrophages.     

Apoptosis during an early stage of nephrogenesis induces renal hypoplasia in bcl-2-deficient mice.

Renal development in bcl-2-deficient mice was monitored to examine the temporal and spatial function of this gene during nephrogenesis in vivo. Extensive apoptosis occurred during abnormal nephrogenesis in bcl-2-deficient mice. In embryos and newborn mice, the sequence of morphological events was monitored by morphology in conjunction with morphometry, and bcl-2 -/-, bcl-2 +/-, and bcl-2 +/+ mice were compared. In bcl-2 -/- mice, initial induction of nephrons was detected by embryonic day 13 (E-13) as normal. Then, apoptotic cells became five times more frequent at E-13 to E-16 with a significant reduction (1/5) in nephron number at E-17 to E-19 in bcl-2 -/- mice compared with bcl-2 +/+ mice. No morphological difference was evident between bcl-2 +/- mice and bcl-2 +/+ mice by morphometry. Apoptotic cells were found mainly among the mesenchyme and less frequently in tubuli. Little apoptosis among ureteric buds was noted. In bcl-2 -/- mice at E-17 to E-19, inactive branching and insufficient convolution of ureteric buds were accompanied by fulminant apoptosis in the mesenchyme. Neonatal bcl-2 -/- mice lacked the nephrogenic zone, exhibiting renal hypoplasia. Thus, bcl-2 seems to inhibit apoptosis in renal stem cells during the induction of nephrons in vivo.     

Effects of retinoic acid on keratinocyte proliferation and differentiation in a psoriatic skin model

Psoriasis is a skin disease characterized by the presence of red plaques on the skin. This pathology is well-known to be a retinoid-sensitive disease. Previous investigations have shown that retinoids can modulate epidermal proliferation with an antiproliferative potential in hyperproliferative skins. The aim of this study was to compare the development of psoriatic substitutes cultured in a retinoic acid supplemented medium with those cultured in medium receiving no supplement, to define the effects of this growth factor on keratinocyte proliferation and differentiation. The self-assembly method was used to create substitutes. Characterization of the psoriatic substitutes was performed by histological and immunolabeling analyses. Results showed that psoriatic keratinocyte substitutes cultured with retinoic acid have a thinner epidermis compared with psoriatic keratinocyte substitutes cultured without this supplement. Further, the expression of all tested cell differentiation markers was restored in psoriatic keratinocyte substitutes cultured in presence of retinoic acid. No significant change in epidermal thickness or in the expression of late differentiation markers was observed in healthy keratinocyte substitutes cultured with or without retinoic acid; however, some changes were reported for proliferation and early differentiation markers. Results suggest that retinoic acid can modulate epidermal differentiation and proliferation with an antiproliferative potential in psoriatic substitutes such as observed in psoriatic skin in vivo.