Role for cellular Src kinase in myoblast proliferation

In this study, a role for cellular Src in muscle cell proliferation and differentiation was investigated. Pharmacological inhibition of Src-class kinases repressed proliferation and promoted differentiation of the C2C12 muscle cell line, even when the cells were cultured under growth-inducing conditions of high serum. Pharmacological inhibition of Src-class kinases also affected cellular components that regulate proliferation and differentiation in muscle; cyclin D1 levels were reduced while, myogenin was increased. Suppression of cyclin D1 and enhancement of myogenin levels also occurred upon expression of a dominant negative Src, corroborating a role for Src kinases in regulating proliferation and differentiation. Inhibition of Src-family kinases also blocked fibroblast growth factor (FGF) induced proliferation but, notably, did not reverse the effect of FGF to inhibit differentiation. Evidence for the Src-class kinase Src in myoblast mitogenesis was obtained by determining the pattern of protein expression and activity for this kinase. Under all conditions examined, Src's expression and enzymatic activity were high in cultures of myoblasts and down-regulated during differentiation. Importantly, Src's activity was rapidly stimulated by mitogen-containing serum and attenuated when myoblasts were switched to low serum-containing differentiation medium. These data indicate that Src is important for maintaining muscle cell proliferation.     

Role of tight junctions in cell proliferation and cancer

The acquisition of a cancerous phenotype by epithelial cells involves the disruption of intercellular adhesions. The reorganization of the E-cadherin/beta-catenin complex in adherens junctions during cell transformation is widely recognized. Instead the implication of tight junctions (TJs) in this process is starting to be unraveled. The aim of this article is to review the role of TJ proteins in cell proliferation and cancer.     

端粒、端粒酶与细胞衰老

端粒和端粒酶是现代生物学研究的热点,端粒的缺失与细胞的衰老,端粒酶的活性与细胞的老化及癌化均有密切的关系。章综述了端粒和端粒酶的结构和功能,及其与细胞衰老的关系,并在此基础之上展望了端粒酶在抗衰老、抑制肿瘤等方面的应用。     

Role of the cellular environment in interstitial stem cell proliferation in Hydra

Summary The role of the cellular environment on hydra stem cell proliferation and differentiation was investigated by introduction of interstitial cells into host tissue of defined cellular composition. In epithelial tissue lacking all non-epithelial cells the interstitial cell population did not grow but differentiated into nerve cells and nematocytes. In host tissue with progressively increased numbers of nerve cells growth of the interstitial cell population was positively correlated to the nerve cell density. In agreement with previous observations (Bode et al. 1976), growth of the interstitial cell population was also found to be negatively correlated to the level of interstitial cells present. The strong correlation between the growth of the interstitial cell population and the presence of interstitial cells and nerve cells implies that interstitial cell proliferation is controlled by a feedback signal from interstitial cells and their derivatives. Our results suggest that the cellular environment of interstitial cells provides cues which are instrumental in stem cell decision making. Offprint requests to: T.C.G. Bosch     

A highly selective telomerase inhibitor limiting human cancer cell proliferation.

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.     

Role of DNA aneuploidy, overexpression of p53 gene product, and cellular proliferation in the progression of gastric cancer.

DNA aneuploidy, p53 overexpression, and high cell proliferation frequently occur in gastric cancer. However, little is known about the time of their appearance throughout cancer progression. Therefore, the objective of the present study was to determine when such abnormalities occur during gastric cancer progression. We classified the gastric cancers examined into intestinal (n = 65) and diffuse (n = 34) types. DNA ploidy was examined using flow cytometry and expression of MIB-1 and p53 immunoreactivity were studied using the avidin-biotin complex method in three stages of gastric cancer (mucosal, submucosal, deeply invasive cancer, i.e., advanced cancer). The incidence of DNA aneuploidy in intestinal-type mucosal cancers (15/27, 55.6%) was lower than that of submucosal invasive cancers (14/16, 87.5%) or advanced cancers (19/22, 86.4%), while a low incidence of DNA aneuploidy was observed in each diffuse-type cancer group (mucosal, 1/12, 8.3%; submucosal invasive, 3/9, 33.3%; advanced, 8/14, 57.1%). Although overexpression of the p53 gene in intestinal-type cancer was found in early stage, that in diffuse-type cancer was observed in advanced stage. Among the intestinal-type mucosal cancers, the MIB-1 percent positive was higher in aneuploid tumors than diploid ones. DNA aneuploidy and overexpression of the p53 gene may play an important role in the early tumorigenesis of intestinal-type gastric cancer and in the late event of tumorigenesis of diffuse-type gastric cancer.     

Kinetics of cellular proliferation and hormonal receptors in EVSA-T breast cancer cell line.

The hormone-independent human breast cancer cell line EVSA-T, originally described as negative estrogen and progesterone receptors is shown to become positive hormone receptors when the cellular proliferation rate is slowed down. The experimental procedure included the following steps: 1) EVSA-T cells were seeded in minimum essential medium supplemented with 10% fetal bovine serum and kept undisturbed for 2 days; 2) culture medium was replaced with Dulbecco's solution and Ham's F-12 and cells were incubated in serum-free media for another 24 h; 3) then, cells were "rescued" with 10% FBS supplemented medium and estrogen (ER) and progesterone receptors (PgR) were measured immediately, time 0, and 6, 12, 18, 24 and 30 h after the media were changed. Cell yield was quantified at the same times. Experimental data indicate that changing the proliferation kinetics makes it possible to detect estradiol and progesterone receptors on EVSA-T cells. Estrogen receptor appeared at 18 h after rescue, 6 hours before progesterone receptor could be detected. Immunohistochemical analysis of ER content confirmed this observation, showing maximal positive stain at 18 h. Furthermore, ER disappeared when cells recovered their normal proliferation rate.     

Role of Sciellin in gallbladder cancer proliferation and formation of neutrophil extracellular traps

Apart from primary tumor development and metastasis, cancer-associated thrombosis is the second cause of cancer death in solid tumor malignancy. However, the mechanistic insight into the development of gallbladder cancer (GBC) and cancer-associated thrombosis remains unclear. This study aimed to investigate the mechanistic role of Sciellin (SCEL) in GBC cell proliferation and the development of venous thromboembolism. The expression level of SCEL was determined by immunohistochemical staining. Roles of SCEL in gallbladder cancer cell were determined by molecular and cell biology methods. SCEL was markedly upregulated in GBC and associated with advanced TNM stages and a poor prognosis. Furthermore, SCEL interacted with EGFR and stabilized EGFR expression that activates downstream PI3K and Akt pathway, leading to cell proliferation. In addition, SCEL induces tumor cell IL-8 production that stimulates the formation of neutrophil extracellular traps (NETs), accelerating thromboembolism. In xenografts, SCEL-expressing GBCs developed larger tumors and thrombosis compared with control cells. The present results indicate that SCEL promotes GBC cell proliferation and induces NET-associated thrombosis, thus serving as a potential therapeutic target.Subject terms: Cancer microenvironment, Tumour biomarkers     

Evolving views of telomerase and cancer

The maintenance of telomeres, nucleoprotein structures that constitute the ends of eukaryotic chromosomes, regulates many crucial cellular functions and might, in multicellular organisms, participate in the control of complex phenotypes such as aging and cancer. Stabilization of telomere length is strongly associated with cellular immortalization, and constitutive telomerase activation occurs in most human cancers. Such observations form the basis for the prevailing model that postulates that alterations in telomere biology both suppress and facilitate malignant transformation by regulating genomic stability and cell life span. However, recent findings suggest that telomere maintenance might not be an obligate requirement for initial tumor formation in some settings and that telomerase activation contributes to tumorigenesis independently of its role in maintaining telomere length. These recent developments indicate that our understanding of telomere biology remains incomplete and implicate additional complexity in the relationships among telomeres, telomerase and cancer.     

Prohibitin对非小细胞肺癌细胞增殖和凋亡的影响

目的:研究Prohibitin对非小细胞肺癌株A549和NCI-H460细胞增殖和凋亡的影响.方法:将针对Prohibitin的特异性的干扰片段瞬时转染非小细胞肺癌A549和NCI-H460细胞株,以瞬时转染与Prohibitin没有同源性的干扰片段的细胞作为阴性对照,通过免疫蛋白印迹检测各组细胞Prohibitin和Survivin蛋白的表达情况,通过MTT法检测各组细胞的增殖情况,通过流式仪检测各组细胞的凋亡率.结果:针对Prohibitin基因设计的siRNA片段特异性地沉默该基因的表达,与对照组相比较,干扰组的细胞的增殖活性明显增强.同时与凋亡密切相关的Survivin的表达在沉默掉prohibitin后,在A549和NCI-H460中分别降低了46.3%和54.5%.而干扰prohibitin后导致A549细胞的凋亡率上升了约2%.结论:Prohibitin能显著抑制非小细胞肺癌A549和NCI-H460细胞的增殖,而对凋亡的影响可能并不是通过survivin介导的.     

NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer

Nucleotide-binding domain, leucine-rich-repeat–containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication in Nature, we identified NLRC3 as a negative regulator of PI3K–mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K–mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K–mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K–AKT targets FoxO3a and FoxO1 in the colon of Nlrc3^?/? mice, suggesting that additional signaling pathways contribute to increased cellular proliferation. Moreover, NLRC3 suppresses colorectal tumorigenesis by promoting cellular apoptosis. Genes encoding intestinal stem cell markers BMI1 and OLFM4 are upregulated in the colon of Nlrc3^?/? mice. Herein, we discuss recent findings and explore mechanisms through which NLRC3 regulates PI3K–mTOR signaling. Our studies highlight the therapeutic potential of modulating NLRC3 to prevent and treat cancer.     

Cellular proliferation and telomerase activity in CHRF-288-11 cells

Telomerase activity is detected in many immortalized cell lines. Recent studies suggest that terminal differentiation of some of these cell lines is associated with a reduction in telomerase activity. However, the question remains whether the reduction in telomerase activity results from terminal differentiation or from cessation of cellular proliferation. This was explored in the megakaryocytic cell line CHRF-288-11. Cells were treated with phorbol 12-myristate 13-acetate (PMA), which induces terminal differentiation of CHRF-288-11 cells, EGTA, serum depletion, and okadaic acid. All treatments resulted in cessation of proliferation. Except for okadaic acid, these treatments also induced inhibition of telomerase within 7 days. Restoring the original growth conditions of cells treated with PMA, EGTA and serum depletion resulted in the reversal of telomerase inhibition and an acceleration of proliferation. Apparent inhibition of telomerase was observed to follow the cessation of proliferation, whereas enhanced telomerase activity was noted to precede acceleration in proliferation. Thus, telomerase activity usually reflects the proliferative status rather than the differentiated status of CHRF-288-11 cells.