Induction of apoptosis in chronic lymphocytic leukemia cells and its prevention by phorbol ester

Forbes, Ian J.; Zalewski, Peter D.; Giannakis, C.; Cowled, Prue

doi:10.1016/0014-4827(92)90393-m

Cited by 103 publications

(41 citation statements)

References 28 publications

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“…For example, protein phosphatase 2A regulates Akt/ protein kinases B and C and mTOR, all of which promote cell survival (51)(52)(53). Similarly, protein kinase C, which is inhibited by staurosporine, has been implicated in neoplastic transformation (54), regulation of apoptosis (55), and multidrug-resistant phenotype (56). Because our results show that okadaic acid and staurosporine induce AP-2␣-dependent apoptosis, it is possible that protein phosphatase 2A-and protein kinase C-regulated growth promoting, anti-apoptotic, and tumorigenic signaling pathways could lead to AP-2␣ functional inactivation in AP-2␣-overexpressing cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis Induction by Activator Protein 2α Involves Transcriptional Repression of Bcl-2

Wajapeyee¹,

Britto

Ravishankar

et al. 2006

Journal of Biological Chemistry

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Activator protein 2␣ (AP-2␣) 3 is a sequence-specific DNA binding transcription factor that is required for normal growth and morphogenesis (1-3). AP-2␣ has a conserved C-terminal DNA binding motif with an integral helix-span-helix homodimerization motif and a less-conserved proline and aromatic amino acid-rich helix transactivation domain near the N terminus and binds to a consensus DNA sequence, 5Ј-GCCNNNGGC-3Ј (4 -8). AP-2␣ has been shown to regulate many genes involved in variety of biological functions (9).Several lines of evidences indicate that AP-2␣ may act as a tumor suppressor gene. AP-2␣ gene is located in chromosome position 6p22, a region of frequent loss of heterozygosity in breast and other cancers (10). Diminished AP-2␣ function has been correlated with N-Ras oncogene-mediated transformation (11). The functions of AP-2␣ have been shown to be regulated by SV40 T antigen and adenovirus E1A oncoproteins (1, 12). In addition, reduced or loss of AP-2␣ expression has been reported in human cancers of breast, ovary, colon, skin, brain, and prostate (13)(14)(15)(16)(17)(18)(19)(20). In good correlation, expression of dominant negative mutant AP-2␣ resulted in increased invasiveness and tumorigenicity (21).Overexpression of AP-2␣ by transient transfection into cultured cells has been shown to induce p21 WAF1/CIP1 and inhibit cellular DNA synthesis and colony formation (22). Significant correlation between AP-2␣ expression and p21 WAF1/CIP1 has been observed in breast cancer, colorectal cancer, and malignant melanoma (15,18,23). The growth inhibitory activity of AP-2␣ has also been shown to be mediated through direct interaction with p53 (24). Results from our laboratory suggest that adenovirus-mediated overexpression of AP-2␣ inhibits growth of cancer cells by inhibiting cellular DNA synthesis and inducing apoptosis (25). Furthermore, our recent work establishes that AP-2␣ is induced in cancer cells upon treatment with chemotherapeutic drugs, which contributes to chemosensitivity because the simultaneous inhibition of AP-2␣ by siRNA increases the chemoresistance. In addition, the re-expression of epigenetically silenced AP-2␣ in breast cancer resulted in enhanced chemosensitivity and loss of tumorigenicity upon chemotherapy in an AP-2␣-dependent manner (26). These results point out the importance of apoptosis induction by AP-2␣ for its functions, particularly the role in chemosensitivity.The molecular mechanism by which AP-2␣ induces apoptosis is not known. In the present study we have analyzed the pathways and various molecules involved in AP-2␣-induced apoptosis. We found that AP-2␣-induced apoptosis requires primarily the mitochondrial pathway involving a bax/cytochrome c/Apaf1/caspase 9-dependent mechanism. We also found that AP-2␣ binds to the Bcl-2 promoter leading to its transcriptional down-regulation and is essential for the apoptosis induction by AP-2␣. In addition, we provide evidence that the overexpressed AP-2␣ (perhaps functionally inactive) in certain breast cancer cells can be made functio...

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Section: Discussionmentioning

confidence: 99%

Apoptosis Induction by Activator Protein 2α Involves Transcriptional Repression of Bcl-2

Wajapeyee¹,

Britto

Ravishankar

et al. 2006

Journal of Biological Chemistry

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“…Phorbol esters and other activators of PKC inhibit endonuclease activation in thymocytes [56], normal [57] and leukemic [58,59] B cells, a human mammary adenocarcinoma cell line (BT-20) [60], human synovial cells [61], IL-3-dependent hematopoietic cells [62] and kidney epithelial cells [63]. Phorbol esters can also block TNF-mediated apoptosis, presumably due to their effects on the ceramide pathway to apoptosis [60,64].…”

Section: Protein Kinase Cmentioning

confidence: 99%

Signal Transduction Pathways in Apoptosis

1996

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Abstract. Emerging evidence indicates that apoptosis is regulated by some of the same signal transduction pathways previously implicated in other physiological cellular responses, including alterations in intracellular Ca 2+ compartmentalization, activation of protein kinases and phosphatases, alterations in pH and oxidative stress. Interestingly, signals that promote apoptosis in one model can suppress cell death in another, indicating that cellular responses are determined by the intrinsic programming of the cell in question. This review will summarize current knowledge of the signal transduction pathways regulating apoptosis and discuss how they may be coupled to components of the molecular machinery for cell death.

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“…Today glucocorticoids are common components in many chemotherapeutic protocols for lymphoid malignancies, including multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma (3)(4)(5)(6). In fact, glucocorticoid therapy is essential for the successful treatment of childhood acute lymphoblastic leukemia (5).…”

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confidence: 99%

Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced Apoptosis

Wang¹,

Malone²,

He³

et al. 2003

Journal of Biological Chemistry

198

223

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Despite being one of the earliest recognized and most clinically relevant forms of apoptosis, little is known about the transcriptional events that mediate glucocorticoid-induced apoptosis. Therefore, we used oligonucleotide microarrays to identify the pattern of dexamethasone-induced changes in gene expression in two well characterized models of glucocorticoid-induced apoptosis, the murine lymphoma cell lines S49.A2 and WEHI7.2. Dexamethasone treatment induced a diverse set of gene changes that evolved over a 24-h period preceding the onset of cell death. These include previously reported changes in the expression of genes regulating prosurvival signals mediated by c-Myc and NFB. Unexpectedly, we discovered that glucocorticoid treatment increases expression of the gene encoding Bim, a BH3-only member of the Bcl-2 family that is capable of directly activating the apoptotic cascade. Induction of Bim was confirmed by immunoblotting not only in S49.A2 and WEHI7.2 cells but also in the human leukemia cell line CEM-C7 and in primary murine thymocytes. All three prototypical isoforms of Bim (Bim EL , Bim L , and Bim S ) were induced by dexamethasone. Because elevated expression of Bim initiates the execution phase of cell death, this report that Bim is induced by dexamethasone provides novel insight into the mechanism through which glucocorticoid-mediated changes in gene expression induce apoptosis in lymphoid cells.

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Induction of apoptosis in chronic lymphocytic leukemia cells and its prevention by phorbol ester

Cited by 103 publications

References 28 publications

Apoptosis Induction by Activator Protein 2α Involves Transcriptional Repression of Bcl-2

Apoptosis Induction by Activator Protein 2α Involves Transcriptional Repression of Bcl-2

Signal Transduction Pathways in Apoptosis

Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced Apoptosis

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