Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells

Real, Pedro J.; Sanz, Cristina; Gutiérrez, Olga; Pipaón, Carlos; Zubiaga, Ana M.; Fernández-Luna, José L.

doi:10.1016/j.febslet.2006.08.088

Cited by 33 publications

(33 citation statements)

References 20 publications

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“…Of interest were genes of the BCl-2 pathway: BCl-2 associated transcription factor (up-regulated) and BCl-2 interacting killer (down-regulated, which is a novel, highly potent death inducing gene; refs. 30,31). Also, down-regulated genes were retinoic acid receptor-responsive gene, p21 (Ras activator), CDC27 (mitochondrial tumor suppressor), interleukin-1-associated kinase, kinetochore-associated protein (crucial for telophase), and retinoblastoma binding protein-1 (a suppressor of Rb protein).…”

Section: Discussionmentioning

confidence: 99%

Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA

et al. 2008

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CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. We have shown that CD24 is overexpressed in 90% of colorectal tumors at a fairly early stage in the multistep process of carcinogenesis. Anti-CD24 monoclonal antibodies (mAb) induce a significant growth inhibition in colorectal and pancreatic cancer cell lines that express the protein. This study is designed to investigate further the effects of CD24 down-regulation using mAb or small interfering RNA in vitro and in vivo. Western blot analysis showed that anti-CD24 mAb induced CD24 protein down-regulation through lysosomal degradation. mAb augmented growth inhibition in combination with five classic chemotherapies. Xenograft models in vivo showed that tumor growth was significantly reduced in mAb-treated mice. Similarly, stable growth inhibition of cancer cell lines was achieved by down-regulation of CD24 expression using short hairpin RNA (shRNA). The produced clones proliferated more slowly, reached lower saturation densities, and showed impaired motility. Most importantly, down-regulation of CD24 retarded tumorigenicity of human cancer cell lines in nude mice. Microarray analysis revealed a similar pattern of gene expression alterations when cells were subjected to anti-CD24 mAb or shRNA. Genes in the Ras pathway, mitogenactivated protein kinase, or BCL-2 family and others of oncogenic association were frequently down-regulated. As a putative new oncogene that is overexpressed in gastrointestinal malignancies early in the carcinogenesis process, CD24 is a potential target for early intervention in the prevention and treatment of cancer. [Cancer Res 2008;68(8):2803-12]

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Section: Discussionmentioning

confidence: 99%

Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA

et al. 2008

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“…Thus, it is possible that these cellular transcription factors may contribute to transcriptional activation of Bik in Ad-infected cells. Recently, it was reported that in certain cancer cells treated with the chemotherapeutic drug adriamycin, Bik was activated by E2F1 (34). It has previously been shown that expression of Bik was activated in cells infected with an Ad vector that expressed the p53 transgene from the E1 region, suggesting that Bik might be a transcriptional target for p53 (24).…”

Section: Discussionmentioning

confidence: 99%

“…The possibility that E1A might act synergistically with different anticancer drugs through activation of expression of apoptotically enhanced BIK would be of much interest with regards to the use of Ads as oncolytic agents. In this context, activation of BIK expression has also been observed in cells treated with certain anticancer drugs, such as doxorubicin (32) and adriamycin (34). The use of proteasomal inhibitors is on the rise for treatment of neoplastic diseases (19).…”

Section: Discussionmentioning

confidence: 99%

Evidence for Involvement of BH3-Only Proapoptotic Members in Adenovirus-Induced Apoptosis

Subramanian

Vijayalingam

Lomonosova

et al. 2007

J Virol

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Adenovirus (Ad) is a good model system to study the molecular mechanisms involved in cellular processes. During Ad replication, the infected quiescent cells enter into an S-phaselike state resulting in cell proliferation. This cellular environment facilitates the replication of viral DNA. The expression of viral immediate-early gene E1A is essential for the activation of cellular DNA synthesis and for facilitating viral DNA replication. The unscheduled DNA replication induced by E1A (i.e., cellular and viral) appears to contribute to the apoptotic response. It is well established that the apoptotic response induced during Ad infection is apparent in cells infected with viral mutants defective in E1B-19K (19,000-molecular-weight protein) (33,37,39,45). These results have indicated that during normal Ad infection virus-induced apoptosis is suppressed by the E1B-19K protein. The cell death response in cells infected with an Ad recombinant virus that expresses the cellular antiapoptosis protein BCL-2 from the E1B region (i.e., in the absence of E1B-19K) is strongly suppressed (38). Similarly, the cytocidal effect of E1B-19K mutant virus is much reduced in cells that ectopically overexpress BCL-2 (7, 40). Thus, the apoptosis-like cell death induced by E1A can be suppressed by overexpression of the cellular BCL-2 protein.The intermediate steps in the Ad-induced cell death pathway that lie between the actions of E1A and E1B-19K are not fully understood. In the canonical apoptotic cell death pathway, the various apoptotic stimuli activate functional expression of one or more members of a class of BCL-2 family proapoptotic proteins known as the BH3-only proteins. The BH3-only proteins (such as BIK, BIM, PUMA, etc.) function as the initiators of the apoptotic paradigm and activate a second class of proapoptotic proteins known as BH123 proteins (such as BAX and BAK) by unknown mechanisms. The BH123 proteins cause the cellular demise via mitochondrial dysfunction and ensuing activation of the caspases (reviewed in reference 12). Although E1B-19K efficiently inhibits the manifestation of the terminal apoptotic phenotypes, such as premature cell death and associated fragmentation of chromosomal DNA, it is unclear at what step in the apoptotic paradigm E1B-19K acts. Similarly, it is also unclear what proapoptotic initiators mediate Ad-induced apoptosis.

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“…Interestingly, the accumulation of E2F1 protein in mouse embryo fibroblasts (MEFs) following cisplatin treatment seems to occur independently of their p53 genetic status (84,86). E2F1 activation results in the transcriptional upregulation of critical pro-apoptotic genes, such as Bik and Bim, and the transcriptional repression of distinct anti-apoptotic family members, including Bcl-2 (82,83,(87)(88)(89)(90)(91). According to this, and since the exposed to the higher dose of cisplatin RT4 and T24 cells were both characterized by a Bik and Bim strong transactivation response, paralleled with a severe downregulation of Bcl-2 gene (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Konstantakou

Voutsinas²,

Karkoulis³

et al. 2009

Int J Oncol

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Abstract.Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNAPt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Fas, FasL, TRAIL, Puma, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells. IntroductionWith its incidence continuing to increase, bladder cancer is classified among the five most common malignancies in industrialized countries (1). Forming a worldwide estimate over one million patients, bladder cancer is clearly considered a significant public health issue around the world (2). The three main types of cancer affecting bladder are transitional cell carcinoma (TCC), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), with TCC representing >90% of all bladder cancers. Four clinically distinct entities of TCC have been recognized: superficial, papillary tumors (Ta and T1), carcinoma in situ (Tis), muscle-invasive tumors (T2-T4) and advanced disease, involving extra-pelvic nodal or distant metastasis (3,4). Metastatic TCC demonstrates a moderate sensitivity to chemotherapy while a significant variation in patient survival rates and activity levels of individual regimens has been observed (5).Cisplatin-based combination chemotherapy protocols, such as MVAC (methotrexate-vinblastine-adriamycin-cisplatin), constituted for a number of years standard treatment of patients with advanced (or metastatic) urothelial bladder cancer. However, due to the MVAC-induced systemic toxici...

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Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells

Cited by 33 publications

References 20 publications

Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA

Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA

Evidence for Involvement of BH3-Only Proapoptotic Members in Adenovirus-Induced Apoptosis

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

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