Gene/Protein Disease Symptom Drug Enzyme Compound
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Apoptosis and the apoptosis-regulatory gene bcl-2 have been suggested from animal studies to be important during the development of the central nervous system (CNS), but information on apoptotic activities of the developing human CNS has been scarce. To establish spatial and temporal distributions of apoptotic cells and Bcl-2 oncoprotein expression, we examined sections taken from cerebral cortex, hippocampus and brainstem at weeks 14, 18, 27, and 32 of gestation. Terminal transferase-mediated nick end labelling (TUNEL), histological analyses, and immunocytochemical staining using monoclonal antibodies were employed. Except for layer I of the motor cortex and the molecular layer of the hippocampus, both at week 14 of gestation, TUNEL-positive cells with typical apoptotic appearance and apoptotic indices, ranging from 0.08 to 2.85, were found in all other brain regions examined including visual, sensory, frontal and motor cortices, hippocampus, dorsal raphe, locus coeruleus, and periaqueductal grey of the brainstem. No specific spatial or temporal distribution patterns of apoptotic cells were found in the cortices. However, the apoptotic index of the molecular layer of the hippocampus increased with the gestation age. The periaqueductal grey of the brainstem showed high apoptotic indices (ranging from 0.37 to 2.85) at all the gestation ages studied. An inverse correlation between apoptosis and Bcl-2 oncoprotein expression was found in visual, sensory, and motor cortices but not in the frontal cortex and hippocampus. Apoptosis and Bcl-2 oncoproteins are important for CNS development and, apart from being an apoptosis regulator, Bcl-2 oncoproteins may also have other roles to play during neural development.
Anat Rec 1998 10
PMID:Apoptosis and Bcl-2 oncoprotein expression in the human fetal central nervous system. 977 71

Apoptosis is an important mechanism in organogenesis, but its role in heart development has been poorly characterized. We have here studied apoptosis in the developing ventricular wall of mouse embryonic heart. Developing mice hearts on days 11 to 16 of gestation were studied using in situ end-labeling of degraded DNA (TUNEL), immunocytochemistry of regulatory genes Bcl-2 and Bax, and light and electron microscopy. TUNEL end-labeled apoptotic cells were found in the ventricular wall on days 11 to 16 of gestation. The proportions of apoptotic cells of all cells in the ventricular wall differed between the trabecular and compact regions (P = 0.003) and between the days of gestation (P = 0.0001), the calculated apoptotic index was greater in the compact region at all ages except day 14. Ultrastructural analysis showed typical apoptotic shrinkage, chromatin degradation, and apoptotic bodies in several myoblastic and myocardial endothelial cells which were also positive by DNA end-labeling. Immunocytochemical reaction for the apoptosis checkpoint proteins in the ventricular wall showed clearly more Bcl-2 positive cells than Bax positive cells. The numerical densities of all cells in the compact and trabecular regions remained always higher in the compact region (P = 0.04) despite the fact that apoptosis was present in both areas at the same time. In conclusion, apoptosis takes place in the developing myocardial muscle as well as the myocardial endothelium during ventricular morphogenesis on days 11 through 16 and decreases clearly on day 16. We suggest that apoptosis and its regulatory factors are closely involved in the morphogenesis of the ventricular wall of the mammalian heart.
Anat Rec 1999 10 01
PMID:Apoptosis in the pattern formation of the ventricular wall during mouse heart organogenesis. 1048 19

Smad 3 is a signaling intermediate for the transforming growth factor beta (TGFbeta) family; however, little is known about the role this protein plays in the regulation of the ovarian surface epithelium (OSE). Using a transgenic mouse model, we found that in the absence of Smad 3 there was a distinct morphological alteration of OSE cells. Wild-type (WT) OSE was flat with thin cells, while Smad 3-deficient (Smad 3 -/-) OSE was thick with plump cuboidal cells. WT OSE had less immunostaining for proliferating cell nuclear antigen (PCNA) and estrogen receptor alpha (ERalpha) than Smad 3 -/- OSE. However, there were no differences in the number of apoptotic cells or Bax and Bcl-2 levels between WT and Smad 3 -/- OSE. Although WT mice had higher levels of serum estradiol than Smad 3 -/- mice, WT and Smad 3 -/- mice had similar levels of progesterone. These data suggest that Smad 3 regulates OSE morphological appearance and proliferation in the absence of high serum estradiol levels or alterations in progesterone levels.
Anat Rec A Discov Mol Cell Evol Biol 2003 Aug
PMID:Smad 3 regulates proliferation of the mouse ovarian surface epithelium. 1284 4

Aging cartilage displays increased chondrocyte apoptosis and decreased responsiveness of chondrocytes to growth factors. The molecular mechanisms responsible for these changes have not been identified. Bag-1 is a Bcl-2-binding protein that promotes cell survival, interacts with a diverse group of cellular proteins, and may integrate multiple pathways involved in controlling cell survival, growth, and phenotype. Bcl-2 is important for maintaining chondrocyte phenotype and delaying terminal differentiation and apoptosis of chondrocytes. Comparatively little is known about the role of Bag-1 in cartilage. Here we show that both growth plate and articular chondrocytes in the mouse express the Bag-1 protein. In the growth plate, Bag-1 expression is prominent in the late proliferative and prehypertrophic chondrocytes, displaying a pattern similar to what has been reported for Bcl-2. Further, the expression of both Bcl-2 and Bag-1 declines with age in the articular cartilage. Growth assays demonstrate that knocking down Bag-1 expression causes a decrease in growth rate. These results suggest that Bag-1 is involved in the regulation of chondrocyte phenotype and cartilage aging.
Anat Rec A Discov Mol Cell Evol Biol 2004 Aug
PMID:Age-related expression patterns of Bag-1 and Bcl-2 in growth plate and articular chondrocytes. 1527 42

The migration of macrophages and lymphocytes that produce cytokines such as tumor necrosis factor-alpha (TNF-alpha) causes beta-cell death, leading to type 1 diabetes. Similarly, in type 2 diabetes, the adipocyte-derived cytokines including TNF-alpha are elevated in the circulation, causing inflammation and insulin resistance. Thus, the studies described in this article using TNF-alpha are relevant to furthering our understanding of the pathogenesis of diabetes mellitus. We used RINr1046-38 (RIN) insulin-producing beta-cells, which constitutively express calbindin-D(28k), to characterize the effect of TNF-alpha on apoptosis, replication, insulin release, and gene and protein expression. Western blots of TNF-alpha-treated RIN cells revealed a decrease in calbindin-D(28k). By ELISA, TNF-alpha-treated beta-cells had 47% less calbindin-D(28k) than controls. In association with the decline in calbindin-D(28k), TNF-alpha treatment of RIN cells led to a 73% greater increase in changes in intracellular calcium concentration (Delta[Ca(2+)](i)) in TNF-alpha-treated cells as compared to that in control RIN cells upon treatment with 50 mM KCl; caused a greater increase in the [Ca(2+)](i) following the addition of 5.5 microM ionomycin; increased by more than threefold the apoptotic rate, expressed as the percentage of TUNEL-positive nuclei to total nuclei; decreased the rate of cell replication by 36%; and increased and decreased selectively the expression of specific genes as determined by microarray analysis. The subcellular localizations of Bcl-2, an antiapoptotic protein, and Bax, a proapoptotic protein, within RIN cells were altered with TNF-alpha treatment such that the two were colocalized with mitochondria in the perinuclear region. We conclude that the proapoptotic action of TNF-alpha on beta-cells is manifested via decreased expression of calbindin-D(28k) and is mediated at least in part by [Ca(2+)](i).
Anat Rec A Discov Mol Cell Evol Biol 2005 Oct
PMID:Tumor necrosis factor-alpha-induced changes in insulin-producing beta-cells. 1611 68

Abnormal hyperphosphorylation of the cytoskeletal protein tau is a characteristic feature of neurodegeneration in Alzheimer's disease (AD) brain. Okadaic acid (OA), a protein phosphatase inhibitor, induces neuronal death and hyperphosphorylation of tau. In the present study using a model of microinjection of OA into rat frontal cortex, we aimed to investigate if OA-induced hyperphosphorylation of tau and neuronal death are related to the expression of Bcl-2, an apoptosis inhibitor, or Bax, an apoptosis inducer. Immunohistochemistry and Western blot analysis showed that OA injection dose- and time-dependently induced the expression of Bcl-2 and Bax protein in the surrounding of OA injection areas, which were similar with that of AT8 immunostaining, a marker of hyperphosphorylated tau. However, the ratios of Bcl-2 over Bax had a negative relationship to the expression of AT8. Furthermore, double fluorescent staining showed that AT8-positive neurons mainly costained with terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick-end labeling, a marker of DNA damage, indicating that tau hyperphosphorylation may be associated with DNA damage in the neurons of rat brain. In the areas more adjacent to the OA injection site, most neurons with AT8-positive staining showed vulnerability to OA toxicity and could be triple-stained with Bcl-2 and Bax or double-stained with Bcl-2. However, in the areas further from the OA injection site, neurons with few AT8-positive staining showed resistance to OA toxicity and only stained with Bcl-2, but not Bax. The results suggest that the ratios of Bcl-2 over Bax expression may have an effect on tau hyperphosphorylation and neuronal death following OA injection.
Anat Rec A Discov Mol Cell Evol Biol 2005 Dec
PMID:Induction of Bcl-2 and Bax was related to hyperphosphorylation of tau and neuronal death induced by okadaic acid in rat brain. 1626 26

It has been clearly established that receptor activator of nuclear factor kappa B ligand (RANKL) is a key cytokine involved in the differentiation of osteoclastic precursors of the monocytic/macrophagic lineage. However, relatively little information is available on the ability of RANKL to modulate the expression of genes controlling cell survival/apoptosis and proliferation in human osteoclastic cells in comparison to macrophages. For this purpose, CD14+ human peripheral blood mononuclear cells, which express the cognate high affinity receptor activator of nuclear factor kappa B (RANK), were differentiated along the macrophagic or osteoclastic lineage by adding macrophage-colony stimulating factor (M-CSF) or M-CSF plus RANKL in culture for 12 days. RANKL up-regulated the expression of the chemokine MIP1alpha, which potentiates osteoclastic differentiation and simultaneously activated both anti-apoptotic (Bcl-2) and pro-apoptotic (CIDEB, PYCARD, and BAK-1) genes. Moreover, RANKL markedly up-regulated cylin D2, while it significantly decreased the levels of cyclin A, cyclin-dependent kinase 2, and other cyclin-dependent kinases, in keeping with the notion that end-stage osteoclasts are nondividing cells. Finally, a long-term exposure of RANKL up-regulated the adaptor protein TRAF3 but not TRAF6.
Anat Rec (Hoboken) 2007 Jul
PMID:Receptor activator of nuclear factor kappa B ligand (RANKL) modulates the expression of genes involved in apoptosis and cell cycle in human osteoclasts. 1750 59

Mechanisms of cisplatin resistance in cancer cells are not fully understood. Here, we showed a critical role for the chloride channel-3 (ClC-3) in cisplatin resistance in human erythroleukemia K562 and RK562 cells. We found that a chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) could protect cells from cisplatin-induced apoptosis. NPPB treatment decreased the mRNA and the protein expression of Bax/Bcl-2, decreased the protein expressions of cytochrome C and caspase-3, and increased the mRNA expressions of cyclin D1 and ClC-3 in cells treated with cisplatin. The caspase-3 activity was decreased significantly and the rate of cell apoptosis was decreased. NPPB treatment increased CIC-3 expression, which could increase acidification of intracellular compartments, and increased sequestration of cisplatin, inducing decreased effective drug concentrations, and subsequently cell death. Collectively, our data indicate that NPPB can induce drug resistance to cisplatin by upregulating the expression of CIC-3. NPPB-induced CIC-3 expression facilitates acidification of sequestrated cisplatin, and plays an important role in preventing cisplatin-induced apoptosis in human erythroleukemia K562 and RK562 cells.
Anat Rec (Hoboken) 2011 Jun
PMID:5-Nitro-2-(3-phenylpropylamino) benzoic acid induced drug resistance to cisplatin in human erythroleukemia cell lines. 2153 33

Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B-35, encoded by lysosomal protein transmembrane 4 beta gene, is overexpressed in over 80% of HCCs and is a novel-independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B-35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication-deficient adenovirus vector-mediated upregulation of LAPTM4B-35 promotes anchorage-independent proliferation and resistance to adriamycin-induced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3-kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl-xL/bcl-2-associated death promoter homolog (Bad) signaling pathway, inhibition of caspase-3 activation, upregulation of Bcl-2, and downregulation of Bax. In addition, upregulation of LAPTM4B-35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo. In conclusion, LAPTM4B-35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B-35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC.
Anat Rec (Hoboken) 2011 Jul
PMID:Upregulation of LAPTM4B-35 promotes malignant transformation and tumorigenesis in L02 human liver cell line. 2161 8

The anti-cancer effects of bryostatin-1, a potent diacylglycerol analogue, have traditionally been attributed to its action on protein kinase C. However, we previously documented apoptosis in a B non-Hodgkin lymphoma cell line involving diacylglycerol analogue stimulation of Ras guanyl-releasing protein, a Ras activator, and Bim, a proapoptotic Bcl-2 family protein. To further explore the role of Bim, we examined several Bim-deficient B non-Hodgkin lymphoma cells for their responses to pico, a synthetic bryostatin-1-like compound. The Bim(-) mantle cell lymphoma cell lines Jeko-1, Mino, Sp53, UPN1, and Z138 and the Bim(+) cell line Rec-1, as well as the Burkitt lymphoma cells lines BL2 (Bim(-)) and Daudi (Bim(+)), were examined for their response to pico using assays for proliferation and apoptosis as well as biochemical methods for Ras guanyl-releasing proteins and Bcl-2 family members. With the exception of UPN1, mantle cell lymphoma cell lines underwent pico-induced apoptosis, as did BL2. In some cases, hallmarks of apoptosis were substantially diminished in the presence of mitogen-activated protein kinase kinase inhibitors. Pico treatment generally led to increased expression of proapoptotic Bik, although the absolute levels of Bik varied considerably between cell lines. A pico-resistant variant of Z138 exhibited decreased Bik induction compared to parental Z138 cells. Pico also generally decreased expression of anti-apoptotic Bcl-XL and Mcl1. Although, these changes in Bcl-2 family members seem unlikely to fully account for the differential behavior of the cell lines, our demonstration of a potent apoptotic process in most cell lines derived from mantle cell lymphoma encourages a re-examination of diacylglycerol analogues in the treatment of this subset of B non-Hodgkin lymphoma cases.
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PMID:Bryostatin analogue-induced apoptosis in mantle cell lymphoma cell lines. 2246 96


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