Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of Akt, or protein kinase B, is frequently observed in human cancers. Here we report that Akt activation via overexpression of a constitutively active form or via the loss of PTEN can overcome a G(2)/M cell cycle checkpoint that is induced by DNA damage. Activated Akt also alleviates the reduction in CDC2 activity and mitotic index upon exposure to DNA damage. In addition, we found that PTEN null embryonic stem (ES) cells transit faster from the G(2)/M to the G(1) phase of the cell cycle when compared to wild-type ES cells and that inhibition of phosphoinositol-3-kinase (PI3K) in HEK293 cells elicits G(2) arrest that is alleviated by activated Akt. Furthermore, the transition from the G(2)/M to the G(1) phase of the cell cycle in Akt1 null mouse embryo fibroblasts (MEFs) is attenuated when compared to that of wild-type MEFs. These results indicate that the PI3K/PTEN/Akt pathway plays a role in the regulation of G(2)/M transition. Thus, cells expressing activated Akt continue to divide, without being eliminated by apoptosis, in the presence of continuous exposure to mutagen and accumulate mutations, as measured by inactivation of an exogenously expressed herpes simplex virus thymidine kinase (HSV-tk) gene. This phenotype is independent of p53 status and cannot be reproduced by overexpression of Bcl-2 or Myc and Bcl-2 but seems to counteract a cell cycle checkpoint mediated by DNA mismatch repair (MMR). Accordingly, restoration of the G(2)/M cell cycle checkpoint and apoptosis in MMR-deficient cells, through reintroduction of the missing component of MMR, is alleviated by activated Akt. We suggest that this new activity of Akt in conjunction with its antiapoptotic activity may contribute to genetic instability and could explain its frequent activation in human cancers.
 ...
PMID:Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. 1239 Nov 52

TRAIL is a member of the tumor necrosis factor superfamily which induces apoptosis in cancer but not in normal cells. Akt1 promotes cell survival and blocks apoptosis. The scope of this paper was to investigate whether a HL60 human leukemia cell clone (named AR) with constitutively active Akt1 was resistant to TRAIL. We found that parental (PT) HL60 cells were very sensitive to a 6 h incubation in the presence of TRAIL and died by apoptosis. In contrast, AR cells were resistant to TRAIL concentrations as high as 2 microg/ml for 24 h. Two pharmacological inhibitors of PI3K, Ly294002 and wortmannin, restored TRAIL sensitivity of AR cells. AR cells stably overexpressing PTEN had lower Akt1 activity and were sensitive to TRAIL. Conversely, PT cells stably overexpressing a constitutive active form of Akt1 became TRAIL resistant. TRAIL activated caspase-8 but not caspase-9 or -10 in HL60 cells. We did not observe a protective effect of Bcl-X(L) or Bcl-2 against the cytotoxic activity of TRAIL, even though TRAIL induced cleavage of BID. There was a close correlation between TRAIL sensitivity and intranuclear presence of the p50 subunit of NF-kappaB. Higher levels of the FLICE inhibitory protein, cFLIP(L), were observed in TRAIL-resistant cells. Both the cell permeable NF-kappaB inhibitor SN50 and cycloheximide lowered cFLIP(L)expression and restored sentivity of AR cells to TRAIL. Our results suggest that Akt1 may be an important regulator of TRAIL sensitivity in HL60 cells through the activation of NF-kappaB and up-regulation of cFLIP(L) synthesis.
 ...
PMID:Constitutively active Akt1 protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and cFLIP(L) up-regulation. 1259 38

Recent investigations have provided important insights into how signaling through the antigen receptors determines whether a cell survives or dies. In T cells, Grb2 and MAP kinases play essential roles in differentiating between apoptotic and survival signals. The PTEN phosphatase and Bim, a pro-apoptotic Bcl-2 family member, regulate apoptosis in both T and B cells. In B cells, antigen receptor-mediated death can be rescued by co-stimulation, in which the roles of protein kinase C and BAFF, a TNF family member, have been recently elucidated. In a recently identified mechanism of regulating inflammation, receptors such as c-mer and glycoproteins such as MFG-E8 were found to participate in the clearance of apoptotic cells.
 ...
PMID:Apoptosis during lymphoid development. 1263 72

The pathologic grade and clinical stage have some restrictions for the evaluation of the prognosis of prostate carcinoma. Recently, the function of genes related to apoptosis and tumor suppressor genes on the development, progression,and prognostic value of prostate carcinoma was paid close attention due to further research on the molecular pathology of prostate cancer. Overexpression of Bcl-2 was found in high malignant patients of prostate carcinoma and related to androgen refraction and resistance against anticancer agents as well. The mutation of p53 was found in prostatic intraepithelial neoplasia(PIN) and prostate cancer. p53 can be used as an independent prognostic factor for prostate cancer. The deletion of PTEN and p27 is an important negative factor of prognosis. Overexpression of p21 and p16 which are inhibition protein of cell cycle have effects on the formation and differentiation of prostate cancer. Fas/FasL system plays an important role in apoptosis of prostatic epithelial cells and takes part in the carcinogenesis of prostate. BRCA1 and p73 also have effects on the genesis and development of prostate cancer.
 ...
PMID:[Recent advances on molecular pathology of prostate carcinoma]. 1275 24

In a number of different cancer including endometrial cancers, tumor suppressor phosphatase tensin homologue (PTEN, a lipid phosphatase) is frequently mutated. PTEN dephosphorylates PI 3-K product, phosphatidylinositol 3,4,5-triphosphate (PIP3), into inactive PIP2 which blocks Akt activation/phosphorylation. In the present study, we have used an endometrial cancer cell line known to possess wild-type PTEN (HEC-1-A) and two mutated inactive PTEN protein cell lines (RL-95-2 and Ishikawa) to investigate importance of PI 3-K/PTEN/Akt survival pathway in endometrial cancers. As hypothesised, results showed high levels of Akt1/2 mRNAs and protein phosphorylation in the two mutated PTEN human endometrial cancer cells. To test the possible involvement of Akt in the regulation of survival factors, Bcl-2, XIAP, cIAP-1 and cIAP-2 expression were measured. cIAP-1 protein expression was high in cells expressing phospho-Akt. XIAP and cIAP-2 protein expression was not influenced by the presence of active Akt. Akt phosphorylation decreased and apoptosis was strongly increased in mutated PTEN human endometrial cancer cells in the presence of PI 3-K inhibitor (Wortmannin) which was accompanied by a down-regulation of cIAP-1 protein. Wortmannin had no effect on wild-type PTEN HEC-1-A cell line. Although, Bcl-2 expression was strongly expressed in mutated-PTEN cells, expression remained stable in the presence of Wortmannin suggesting that Bcl-2 is not regulated by Akt. Overexpression of Akt using a constitutively active Akt expression vector resulted in an up-regulation of cIAP-1 expression. These results suggest a pivotal role of Akt in the regulation of endometrial cancer cell survival through the up-regulation of a specific inhibitor of apoptosis protein.
 ...
PMID:Akt activity in endometrial cancer cells: regulation of cell survival through cIAP-1. 1288 21

Programmed cell death, or apoptosis, is a series of morphologically and biochemically related processes. The extrinsic (death receptor mediated) and intrinsic (mitochondrial-mediated) apoptotic pathways can be triggered by physiological and pharmacological substances. However, other molecular events influence the sensitivity of prostate cancer cells to apoptotic stimuli, leading to marked variations in the responsiveness of prostate cancer cell lines to individual stimuli. Modulation of apoptotic responses by over expression of anti-apoptotic proteins (NF-kappaB, IAPs and Bcl-2), or attenuation of pro-apoptotic proteins (PTEN and Bax) may be responsible for the variations in sensitivity of these cell lines to hormone and chemotherapy. The expression of anti- and pro-apoptotic proteins in some of the widely used in vitro models of prostate cancer is reviewed.
 ...
PMID:Programmed cell death and survival pathways in prostate cancer cells. 1466 Jan 68

Bcl-2 is associated with resistance to radiotherapy in prostate cancer. It was recently demonstrated that transduction of LNCaP prostate cells with the PTEN gene resulted in Bcl-2 downregulation. We hypothesized that forced expression of PTEN in prostate cancer cells would sensitize cells to radiation, downregulate Bcl-2 expression, and potentiate the G2M block induced by radiation. Four cell lines - PC-3-Bcl-2 (Bcl-2 overexpression, deleted PTEN), PC-3-Neo (wild-type Bcl-2, deleted PTEN), LNCaP (Bcl-2 overexpression, deleted PTEN), and DU-145 (wild-type Bcl-2 and PTEN) - were transduced with a recombinant adenovirus-5 vector expressing the human wild-type PTEN cDNA under the control of a human cytomegalovirus promoter (Ad-MMAC). After correction for the effect of Ad-MMAC on plating efficiency, Ad-MMAC treatment reduced the surviving fractions after 2 Gy as follows: PC-3-Bcl-2, from 60.5 to 3.6%; PC-3-Neo, no reduction; LNCaP, from 29.6 to 16.3%; and DU-145, from 32.7 to 25.7%. PTEN expression was associated with the downregulation of Bcl-2 expression in PC-3-Bcl-2 and LNCaP cell lines. Ad-MMAC plus radiotherapy potentiated the G2M block seen with radiotherapy alone only in PC-3-Bcl-2 cells. These findings suggest that overexpression of Bcl-2 result in radioresistance and inability of radiation to cause its typical G2M cell-cycle arrest.
 ...
PMID:Adenoviral-mediated PTEN transgene expression sensitizes Bcl-2-expressing prostate cancer cells to radiation. 1476 30

Prostate cancer is the most frequently diagnosed disease in American men today and the second leading cause of death among them. Transformation and progression towards malignancy in prostate cancer is dependant on the inability of the prostatic epithelial cells to undergo apoptosis rather than on the regulation of proliferation. Molecular targeting of inadequacies in this process of suppression of apoptosis could prove to be of great therapeutic importance for prostate cancer patients. Existence of tissue specific promoters to aid in the delivery of genes with therapeutic potential makes molecular therapy an attractive option. This review discusses salient features of molecules such as, Bcl-2, Bcl-(XL), NF-kappaB, Akt, PTEN and Par-4 that play a significant role in the regulation of prostate cancer and focuses on the prospects of effectively utilizing their potential for the therapy of hormone-sensitive and hormone-resistant prostate cancer.
 ...
PMID:Molecular therapy intervention prospects in prostate cancer. 1496 37

Detecting the presence and diversity of low-level mutations in human tumors undergoing genomic instability is desirable due to their potential prognostic value and their putative influence on the ability of tumors to resist drug treatment and/or metastasize. However, direct measurement of these genetic alterations in surgical samples has been elusive, because technical hurdles make mutation discovery impractical at low-mutation frequency levels (<10(-2)). Here, we describe inverse PCR-based amplified restriction fragment length polymorphism (iFLP), a new technology that combines inverse PCR, RFLP, and denaturing high-performance liquid chromatography to allow scanning of the genome at several thousand positions per experiment for low-level point mutations. Using iFLP, widespread, low-level mutations at mutation frequency 10(-2)-10(-4) were discovered in genes located on different chromosomes, e.g., OGG1, MSH2, PTEN, beta-catenin, Bcl-2, P21, ATK3, and Braf, in human colon cancer cells that harbor mismatch repair deficiency whereas mismatch repair-proficient cells were mutation free. Application of iFLP to the screening of sporadic colon cancer surgical specimens demonstrated widespread low-level mutations in seven out of 10 samples, but not in their normal tissue counterparts, and predicted the presence of millions of diverse, low-incidence mutations in tumors. Unique low-level mutational signatures were identified for each colon cancer cell line and tumor specimen. iFLP allows the high-throughput discovery and tracing of mutational signatures in human cells, precancerous lesions, and primary or metastatic tumors and the assessment of the number and heterogeneity of low-level mutations in surgical samples.
 ...
PMID:Inverse PCR-based RFLP scanning identifies low-level mutation signatures in colon cells and tumors. 1505 10

Prostate cancer is the most common non-cutaneous malignancy in American men and the second greatest cause of cancer-related death. Development of effective therapeutic modalities for the treatment of this cancer relies heavily on understanding the molecular alterations that result in the initiation and progression of the tumorigenic process. Increasing evidence indicates that impaired ability to undergo apoptosis plays an important role in the evolution from androgen-dependent to androgen-independent prostate cancer. In this review, we address recent progress toward the central objectives of understanding the molecular events that contribute to prostate cancer progression. We focus on some key regulatory molecules, including the pro-apoptotic regulators p53, PTEN, caspases and Par-4, and the anti-apoptotic molecules Bcl-2, NF-kappaB and Akt, to discuss their roles in prostate cancer progression and their therapeutic implications in human prostate carcinoma.
 ...
PMID:Apoptosis in prostate cancer: progressive and therapeutic implications (Review). 1520 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>