Bcl-2 and the regulation of programmed cell death

Jc, Reed

doi:10.1083/jcb.124.1.1

Cited by 2,172 publications

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“…The product of the bcl-2 gene has been shown to protect cells against cell death induced by a myriad of insults, including most chemotherapeutic drugs (Reed, 1994). For this reason, it has been hypothesised that bcl-2 overexpression may play a role in resistance to chemotherapy, as has recently been demonstrated for neuroblastomas (Castle et al, 1993) and acute myeloid leukaemia (Campos et al, 1993).…”

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confidence: 99%

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy

Slooten

Clahsen²,

Dierendonck³

et al. 1996

Br J Cancer

105

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Summary The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin-embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0-3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5+6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P<0.001) and progesterone receptor positivity (P<0.001) and low tumour grade (P<0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P<0.001) and c-erb-B-2 positivity (P<0.001), high Ki-67 index (P<0.001), mitotic index (P<0.001) and large tumour size (P=0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3-6) had a significantly better disease-free (P=0.004) and overall (P=0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease-free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P=0.07) and negative (HR=0.55, 95% CI 0.27-1.12, P=0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node-negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series.

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Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy

Slooten

Clahsen²,

Dierendonck³

et al. 1996

Br J Cancer

105

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“…Since Elk-1 functions as a transcriptional regulator, it may be either activating death inducing genes like fos (Preston et al, 1996), Bad, Bax, Bak, BclxL, etc. or repressing death inhibiting genes like Bcl-2 (Oltvai and Korsmeyer, 1994;Reed, 1994). Bcl-xL, Mcl-1, Al, Bag-1, etc.…”

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Induction of apoptosis by Elk-1 and ΔElk-1 proteins

et al. 1998

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Elk-1, an ets related gene codes for at least two splice variants Elk-1, which regulates c-fos transcription and DElk-1, both of which function as transcriptional activators. To investigate the role of Elk-1 and DElk-1 proteins in apoptosis; we have developed rat ®broblast cell lines and human breast cancer cell lines expressing Elk-1 and DElk-1. The expression of Elk-1 and DElk-1 proteins in the Elk-1/DElk-1 transfectants were analysed by immuno¯uorescence, immunohistochemistry, and Western blot analysis. The Elk-1 unlike DElk-1 transfectants showed a shortened and¯attened morphology compared to the parental cells. We have found that calcium ionophore treatment of Rat-1 Elk-1, MCF-7 Elk-1, Rat-1 DElk-1 and MCF-7 DElk-1 transfectants resulted in programmed cell death. These results indicate that constitutive expression of Elk-1 and DElk-1 proteins triggers apoptosis in Rat-1 ®broblasts and breast cancer cells when treated with calcium ionophore.Keywords: Elk-1; DElk-1; apoptosis; calcium ionophore; breast cancer; MCF-7; Rat-1The Elk-1 gene belongs to the ets family of ternary complex factors (TCFs), i.e. Elk-1, SAP1, and NET/ ERP/SAP2/Elk-3 (Rao et al., 1989;Hipskind et al., 1991;Giovane et al., 1994;Lopez et al., 1994;Dalton and Treisman, 1992;Price et al., 1995;Nozaki et al., 1996). The Elk-1 gene codes for at least two alternately spliced products Elk-1 (Rao et al., 1989) and DElk-1 (Rao and Reddy, 1993) which function as transcriptional activators (Rao and Reddy, 1992;Bhattacharya et al., 1993), are substrates for MAP kinases Marias et al., 1993;Hill et al., 1993) and JNK protein kinases (Gupta et al., 1996;Whitmarsh et al., 1995). As mentioned earlier, the Elk-1 protein is a TCF which in association with serum response factor (SRF) forms a ternary complex on the serum response element (SRE) of the c-fos promoter and regulates cfos transcription (Hipskind et al., 1991). The TCF's which includes Elk-1 have three domains with similar sequences and functions. The ets domain mediates DNA binding, the SRF interaction domain interacts with SRF to form a ternary complex with the c-fos SRE and the C-terminal domain activates transcription upon phosphorylation by MAP kinases (Rao et al., 1989;Rao and Reddy, 1992;Dalton and Treisman, 1992;Janknecht et al., 1993Janknecht et al., , 1994Marias et al., 1993;Giovane et al., 1994;Hipskind et al., 1994;Kortenjann et al., 1994;Lopez et al., 1994;Hill et al., 1995;Price et al., 1995;Whitmarsh et al., 1995) and JNK kinases (Gupta et al., 1996). Thus Elk-1 represents a key link between signal transduction and induction of gene transcription.The Gag-Myb-Ets fusion protein, identi®ed in the avian acute leukemia virus E26 was shown to inhibit apoptosis and induce erythroid di erentiation in hematopoietic cells (Athanasiou et al., 1996). Similarly the Ets-1 proto-oncogene was shown to be required for the normal survival and activation of B and T cells while an Ets-1 splice variant was shown to induce apoptosis in human colon cancer cells indicating a role in apoptosis (Bories et al....

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“…Both DOX and VP-16 induce apoptosis (Ling et al, 1993;Lowe et al, 1993). Several oncogenes and tumour-suppressor genes have been identified that regulate the apoptotic cell death, including bcl-2 and related proteins, c-myc and p53 (for review see Reed, 1994; Thompson, 1995). Overexpression of the 26-kDa bcl-2 protein in transfected cell lines prevents apoptosis and confers resistance to a number of cytotoxic anti-cancer agents, including topo II inhibitors (Miyashita and Reed, 1993).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous overexpression of the long form of the Bcl-X protein in a highly resistant P388 leukaemia

Kühl

Krajewski²,

Durán³

et al. 1997

Br J Cancer

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Summary A novel resistant variant of murine P388 leukaemia, P388/SPR, was identified by de novo resistance to doxorubicin (DOX) in vivo. This mutant displayed a similar level of cross-resistance to etoposide (VP-16) and other topoisomerase 11 (topo 11) inhibitors. Further analysis of the phenotype revealed a broad cross-resistance to vinca alkaloids, alkylating agents, antimetabolites, aphidicolin and UV light. Low-level expression of mdrl and P-glycoprotein (P-gp), as well as a modest impairment of cellular drug accumulation and partial reversion of resistance to DOX and VP-1 6 by cyclosporine, confirmed a moderate role of P-gp in conferring drug resistance in P388/SPR cells. Consistent changes in neither topo 11 expression or activity nor glutathione metabolism could be detected. Induction of apoptosis was significantly reduced in P388/SPR cells, as indicated by minimal DNA fragmentation. Analysis of oncogenes regulating apoptotic cell death revealed a marked decrease of bcl-2 in combination with a moderate reduction of bax protein, but a striking overexpression of the long form of the bcl-X protein. Transfection of human bcl-X-L into P388 cells conferred drug resistance similar to that of P388/SPR cells. The data suggest that overexpression of bcl-X-L results in an unusual phenotype with broad cross-resistance to non-MDR-related cytotoxins in vitro, and provide an interesting example of spontaneous overexpression of another member of the bcl-2 gene family in cancer.Keywords: multidrug resistance; doxorubicin; apoptosis; murine leukaemia; bcl-X The mechanisms of action of doxorubicin (DOX) are complex and include free radical formation (Bachur et al, 1978), membrane effects (Tritton et al, 1978), DNA intercalation and disruption of topoisomerase II (topo II) action (Tewey et al, 1984), as well as induction of apoptosis (Ling et al, 1993). P-glycoprotein (P-gp) and changes in topo II expression or activity are well-known mechanisms of resistance to DOX (Kartner et al, 1985;Deffie et al, 1989;Ganapathi et al, 1989;Baas et al, 1990) (for review see Endicott and Ling, 1989;Hochhauser and Harris, 1993). Other alternative mechanisms include increased glutathione (GSH) levels (Kramer et al, 1988;Rabier et al, 1991) or glutathione-S-transferase (GST) activity (Nakagawa et al, 1990) and inhibition of programmed cell death by overexpression of bcl-2 or loss of p53 (Lowe et al, 1993;Miyashita and Reed, 1993). Resistance to DOX may be multifactorial, with several of these mechanisms involved (Baas et al, 1990;Rabier et al, 1991;Datta et al, 1995).The aforementioned mechanisms have predominantly been studied in cell lines purposely rendered resistant by treatment with increasing drug concentrations in vitro. We report herein a novel resistance phenotype of a variant of the murine P388 leukaemia, which was observed to be resistant to DOX after in vivo passaging without drug selection. Analysis of these drug-resistant leukaemia cells revealed marked overexpression of bcl-X-L, thus providing an example of spontaneously occur...

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Bcl-2 and the regulation of programmed cell death

Cited by 2,172 publications

References 53 publications

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy

Induction of apoptosis by Elk-1 and ΔElk-1 proteins

Spontaneous overexpression of the long form of the Bcl-X protein in a highly resistant P388 leukaemia

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