UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
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PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

beta-Catenin and transcriptional factor TCF-4 (human T-cell factor-4) genes comprise the Wnt signal. The Wnt signal pathway plays an important role in malignant transformation. We hypothesize that the beta-catenin and TCF-4 gene and Wnt signal are important in the progression of renal cell carcinoma (RCC). To test this hypothesis, we investigated TCF-4 splicing isoforms, beta-catenin, and Wnt signal pathway (cyclin D1, c-myc, c-jun, and MMP7) in three RCC cell lines (A498, Caki-1, and Caki-2), 38 primary RCCs, and 29 normal kidney samples. We also analyzed the relationship between TCF-4 gene splicing isoforms, proliferation (proliferating cell nuclear antigen labeling index), and apoptosis [antiapoptotic factors (Bcl-2 and Bcl-x(L)), proapoptotic factors (Bak and Bax), and caspase-3] in RCC samples. In 38 RCC samples, four splicing isoforms of the TCF-4 gene were present in the region between exon 12 and exon 17. Thirty (79%) of 38 RCCs and all (100%) of the normal kidney samples showed mixed isoforms with both long and short reading frames in the COOH-terminal region, whereas the remaining 8 RCC samples showed only the long-form reading frame. Two COOH-terminal-binding protein sites were present only in the long-form reading frame. The eight RCCs that demonstrated only the long reading frame isoform showed early disease progression and poor prognosis. In these 8 RCC samples, down-regulation of cyclin D1, c-myc, c-jun, and MMP7 expression was observed at the mRNA level. In addition, a marked reduction of caspase-3 expression was also found at both the mRNA and the protein level. However, the beta-catenin gene was not overexpressed at the mRNA level and protein level, and mutation and deletion were not observed in exon 3. In these three renal cell lines, there was no significant difference in TCF-4 mRNA expression before and after 5-Aza-2'-deoxycytidine treatment, and there appeared to be no splicing isoforms in the region between exon 1 and exon 11. These findings suggest that alteration in beta-catenin is an infrequent event in RCC. In samples in which beta-catenin was not overexpressed, the target genes of Wnt signal were regulated through TCF-4 splicing isoforms. The imbalance between TCF-4 gene splicing isoforms with long and short reading frames is associated with RCC progression through the inhibition of the apoptotic pathway. We demonstrate for the first time that TCF-4 gene splicing isoforms and the Wnt signal pathway can induce progression of RCC by the inhibition of apoptosis and not by the induction of cell proliferation.
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PMID:The human T-cell factor-4 gene splicing isoforms, Wnt signal pathway, and apoptosis in renal cell carcinoma. 1279 77

Solitary fibrous tumor is a spindle cell tumor first described in the pleura, but also found in multiple extrathoracic sites including the meninges, orbit, nasal and paranasal sinuses. No cases have been previously reported in the cavernous sinus or pituitary fossa. We present the case of a 54-year-old woman who presented with progressive amaurosis. On imaging studies, a widely infiltrative lesion involving the pituitary fossa, sphenoid sinus, cavernous sinus, carotid artery, medial temporal, ethmoid, and pterygoid bones, and extending into the nasopharynx was discovered; impression was a malignant tumor originating in the pituitary fossa. At surgery, the tumor was only partially resectable because of extensive bony invasion and encasement of the carotid artery, and was found to compress but not invade the pituitary gland. Histology showed a spindle cell proliferation with a dense, hyalinized collagenous stroma and dilated vascular spaces, some showing a staghorn-like appearance. Areas of cellular pleomorphism and increased cellularity were present, but few mitoses were identified. Immunohistochemistry showed strong positivity with CD34, factor XIIIa, CD99, and Bcl-2. There was scattered cyclin D1, mib-1, and p53 positivity. Muscle, epithelial, vascular, and melanocytic markers were negative. These results led to the diagnosis of solitary fibrous tumor. The size, extensive invasion, and bony destruction indicated a tumor with at least low malignant potential. The occurrence of solitary fibrous tumors in the pituitary fossa and sinuses of the head and neck is rare, but must be considered in the differential diagnosis of spindle cell lesions in these regions.
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PMID:Widely invasive solitary fibrous tumor of the sphenoid sinus, cavernous sinus, and pituitary fossa. 1280 69

Gossypol, a male contraceptive drug, has been demonstrated to have antiproliferative and antimetastatic effects on many kinds of cancer cells in vitro. HT-29 human carcinoma cell line is one of the most susceptible cell lines to gossypol-induced cell death. Here, it is shown that treatment of HT-29 cells with gossypol not only induces cell cycle arrest on the G0/G1 phase, but also induces apoptosis. With a serial of Western blot analysis, it is revealed that gossypol-induced cell cycle arrest is involved in P21 up-regulation and cyclin D1 down-regulation; gossypol-induced apoptosis triggers down-regulation of anti-apoptosis Bcl-2 members: Bcl-X(L), Bag-1 and Mcl-1, up-regulation of pro-apoptosis Bcl-2 member Bak, activation of caspase-3, -6, -7, -8, and -9, up-regulation of Apaf-1, release of cytochrome c (cyto-c) from mitochondria, and activation of both DFF45 and PARP. Taken together, gossypol-induced cell death initiates extensive alterations of cell cycle and apoptosis proteins. Gossypol-induced apoptosis of HT-29 cells is through first the mitochondrial pathway, then the death receptor pathway, and the mitochondria pathway is, at least in part, involved in cyto-c release.
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PMID:Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. 1281 69

It is unclear whether and how cyclin D1 and/or p21(WAF1/CIP1) dysregulation contribute to ulcerative colitis (UC)-related inflammation and colorectal carcinogenesis. Cases of quiescent UC (QUC; n = 15), active UC (AUC; n = 23), UC-related dysplasia (n = 35) and UC-related colorectal adenocarcinomas (CRCs; n = 11) were studied with cyclin D1 and p21(WAF1/CIP1) immunohistochemistry. The CRCs were also studied with beta-catenin, bcl2, and p53 immunohistochemistry, p53 and k-ras mutation analyses, and cyclin D1 gene fluorescence in situ hybridization. QUC showed cyclin D1 (negative/weak staining) and p21(WAF1/CIP1) (surface epithelial and upper-third crypt staining) expression similar to that of normal colorectum. Moderate or strong cyclin D1 immunostaining was seen in 9% of AUC cases, 40% of dysplasia cases, and 36% of UC-related CRCs. Although these carcinomas showed neither cyclin D1 gene amplification nor any association between k-ras mutation and cyclin D1 overexpression, the latter was closely related to nuclear beta-catenin expression. Increased lower-third crypt p21(WAF1/CIP1) staining was seen in 57% of AUC cases; decreased upper-third crypt p21(WAF1/CIP1) staining, in 23% of dysplasia cases; and absent or weak p21(WAF1/CIP1) staining, in 55% of UC-related CRCs. The latter change was always associated with p53 mutation but could not be related to p53 or bcl2 expression. In conclusion, AUC shows up-regulated cyclin D1 and p21(WAF1/CIP1) expression. Cyclin D1 up-regulation and p21(WAF1/CIP1) down-regulation occur early in UC-related carcinogenesis. Cyclin D1 up-regulation is less common in UC-related CRCs than in sporadic CRCs, and is related to beta-catenin nuclear signaling. p21(WAF1/CIP1) down-regulation is seen at an equal or higher frequency among UC-related CRCs compared with sporadic CRCs and is attributable to p53 mutation.
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PMID:Cyclin D1 and p21 in ulcerative colitis-related inflammation and epithelial neoplasia: a study of aberrant expression and underlying mechanisms. 1282 12

Effects of the histone deacetylase (HDAC) inhibitor MS-275 have been examined in human leukemia and lymphoma cells (U937, HL-60, K562, and Jurkat) as well as in primary acute myelogenous leukemia blasts in relation to differentiation and apoptosis. MS-275 displayed dose-dependent effects in each of the cell lines. When administered at a low concentration (e.g., 1 micro M), MS-275 exhibited potent antiproliferative activity, inducing p21(CIP1/WAF1)-mediated growth arrest and expression of differentiation markers (CD11b) in U937 cells. These events were accompanied by an increase in hypophosphorylated retinoblastoma protein and down-regulation of cell cycle-related proteins including cyclin D1. However, at higher concentrations (e.g., 5 micro M), MS-275 potently induced cell death, triggering apoptosis in approximately 70% of cells at 48 h. In contrast to other HDAC inhibitors such as apicidin, the extrinsic, receptor-mediated pathway played a minimal role in MS-275 lethality. However, MS-275 potently induced a very early (e.g., within 2 h) increase in reactive oxygen species (ROS), followed by the loss of mitochondrial membrane potential (Delta psi(m)) and cytosolic release of cytochrome c. These events culminated in activation of the caspase cascade, manifested by poly(ADP-ribose) polymerase, p21(CIP1/WAF1), p27(KIP), Bcl-2, and retinoblastoma protein degradation. MS-275 exposure also resulted in diminished expression of cyclin D1 and the antiapoptotic proteins Mcl-1 and XIAP. Administration of the free radical scavenger L-N-acetylcysteine blocked MS-275-mediated mitochondrial injury and apoptosis, suggesting a primary role for ROS generation in MS-275-associated lethality. Lastly, U937 cells stably expressing a p21(CIP1/WAF1) antisense construct were significantly more sensitive to MS-275-mediated apoptosis than controls, but they were impaired in their differentiation response. Together, these findings demonstrate that MS-275 exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations.
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PMID:The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. 1283 53

It has been previously demonstrated that human carcinomas express interleukin-2 receptor (IL-2R) alpha, beta, and gamma chains. The beta and gamma chains of IL-2R have intermediate binding affinity for IL-2 and are responsible for the intracellular signaling cascades after IL-2 stimulation. IL-2Ralpha lacks the cytoplasmic domain, but is essential for increasing the IL-2-binding affinity of other receptors. Overexpression of IL-2Ralpha in tumor cells is associated with tumor progression and a poor patient prognosis. To define molecular mechanisms responsible for the effects associated with IL-2Ralpha expression, ex vivo experiments were performed with the squamous cell carcinoma head-and-neck cancer line, PCI-13, which was genetically engineered to overexpress the IL-2Ralpha chain. While IL-2Ralpha-overexpressing PCI-13 cells were capable of forming colonies in soft agar, PCI-13 cells transfected with the control vector or those expressing IL-2Rgamma did not. Consistently, IL-2Ralpha-expressing tumor cells proliferated more rapidly than the control or IL-2Rgamma+ cells, associated with increased levels of cyclins A and D1 and cyclin-dependent kinase (cdk(s)) 2 and 4 proteins. In addition, IL-2Ralpha-expressing cells were significantly more resistant to apoptosis induction by a tripeptidyl proteasome inhibitor (ALLN) and two chemotherapeutic drugs (VP-16 and taxol) than the control or IL-2Rgamma+ cells. Accompanying the drug resistance, high levels of anti-apoptotic Bcl-X(L) and Bcl-2 proteins were found in the mitochondria-containing fraction of IL-2Ralpha-expressing tumor cells. Treatment of IL-2Ralpha-expressing cells with a specific Janus kinase 3 (Jak3) inhibitor decreased expression of cyclin A, cyclin D1, Bcl-X(L), and Bcl-2 proteins. Finally, high levels of ubiquitinated proteins were detected in the proliferating IL-2Ralpha-expressing cells. Our data suggest that increased proliferation rates and decreased drug sensitivity of IL-2Ralpha-expressing tumor cells are responsible for the enhanced tumor aggressiveness and poor clinical prognosis of patients whose tumors express IL-2Ralpha.
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PMID:Overexpression of interleukin-2 receptor alpha in a human squamous cell carcinoma of the head and neck cell line is associated with increased proliferation, drug resistance, and transforming ability. 1285 47

Antizyme (AZ) is known to be a regulator of polyamine metabolism that inhibits ornithine decarboxylase activity and polyamine transport, thus restricting polyamine levels. Transgenic mice with AZ expression targeted to the basal cell layer of the forestomach epithelium by the keratin 5 promoter were used to investigate whether AZ overexpression inhibited uncontrolled cell proliferation in zinc-deficient (ZD) mice and reduced their susceptibility to forestomach carcinogenesis by N-nitrosomethylbenzylamine (NMBA). Four-week-old keratin 5/AZ and wild-type (Wt) littermates were placed on ZD or zinc-sufficient (ZS) diets to form four groups: ZD:AZ, ZD:Wt, ZS:AZ, and ZS:Wt. After 5 weeks, 27-45 mice in each group were treated twice with NMBA and sacrificed 14 weeks later. Independent of zinc intake, AZ mice had significantly lower forestomach tumor incidence and tumor multiplicity than respective Wt littermates (P < 0.001): 21% of ZD:AZ versus 76% of ZD:Wt mice and 3% of ZS:AZ versus 33% of ZS:Wt mice developed tumors. Spermidine content was reduced in NMBA-treated ZD:AZ forestomachs. Zinc deficiency increased the forestomach cell proliferation in Wt mice, but this effect was blocked by AZ. Conversely, apoptosis was substantially higher in control and NMBA-treated ZD:AZ than respective ZD:Wt forestomachs. The restored ZD:AZ forestomach epithelium displayed strong expression of Bax, a proapoptotic protein, and weak staining of cyclin D1 and its catalytic partner Cdk4, key regulatory proteins controlling G(1) to S progression. In contrast, proliferative ZD:Wt forestomach showed strong expression of Bcl-2, an antiapoptotic protein, and overexpression of cyclin D1/Cdk4. Treatment of ZD:Wt mice with alpha-difluoromethylornithine, an inhibitor of ornithine decarboxylase, had similar results to AZ in reducing tumor incidence, spermidine content, decreasing cell proliferation, and increasing apoptosis. These results demonstrate that AZ may act as a tumor suppressor gene stimulating apoptosis and restraining cell proliferation, thereby inhibiting forestomach tumor development. Although effects of AZ on functions other than polyamine metabolism are possible, alterations in polyamines are the most likely explanation for the reduction in tumors, supporting the use of strategies to modulate polyamine levels for cancer chemoprevention in individuals at high risk of developing malignancies of the gastrointestinal tract.
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PMID:Antizyme overexpression in transgenic mice reduces cell proliferation, increases apoptosis, and reduces N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. 1287 89

We have previously shown that arsenic trioxide blocks proliferation and induces apoptosis in human pancreatic cancer cells at low, non-toxic concentrations. The mechanisms of the apoptosis was investigated in MiaPaCa2 and PANC-1 cells that have been previously shown to be responsive to arsenic trioxide. The results show the caspase-3, caspase-7, and caspase-9 are all activated by arsenic trioxide, together with cleavage of the downstream caspase-3 target poly ADP ribose polymerase (PARP). Expression of the anti-apoptosis proteins, Bcl-2 and Mcl-1 expression decreased time-dependently while Bax expression increased. These findings indicate that the Bcl family of proteins, the mitochondrial pathway and activation of the caspase cascade are responsible for arsenic-induced apoptosis. Flow cytometric analysis revealed changes of cell cycle distribution from a G0/G1 phase arrest at 24 hours to G2/M phase arrest at 72 hours following arsenic treatment. The sub-G0/G1 cell population of apoptotic cells was increased at these times. Arsenic increased expression of the P21 protein and decreased levels of cyclin A, cyclin B1 and cyclin D1, but expression of CDK2, CDK4, CDK6, and cyclin E were not affected. Arsenic trioxide markedly enhanced the expression of GADD45 and GADD153 in a time-dependent manner. In summary, arsenic trioxide induced apoptosis in pancreatic cancer cells through activating the caspase cascade via the mitochondrial pathway, GADD expression and by modifying cell cycle progress and changes in several cycle-regulating proteins. This old drug may be valuable for treatment of pancreatic cancer.
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PMID:Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression. 1288 67

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.
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PMID:Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis. 1292 Feb 17

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