PubMed · 15958607
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Pavan Bachireddy, Pavan K Bendapudi, Dean W Felsher. 2005-06-15. Getting at MYC through RAS.. https://doi.org/10.1158/1078-0432.ccr-05-0534
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Members of the BCL-2 gene family are well known for their role in the pathogenesis of B-cell lymphomas in humans and in mouse models. A recent report that knockout mice deficient for the proapoptotic BCL-2 family member gene BAD frequently develop B-cell lymphomas prompted us to analyze a large collection of human B-cell lymphomas for inactivating mutations in the BAD gene. All 3 exons of the BAD gene were amplified and directly sequenced. The 81 lymphomas analyzed included 16 cases of B-cell chronic lymphocytic leukemia, 11 mantle-cell lymphomas, 10 follicular lymphomas, 7 MALT lymphomas, 8 Burkitt's lymphoma cell lines, 3 cell lines of multiple myeloma, 15 cases and 4 cell lines of diffuse large B-cell lymphoma and 7 Hodgkin's lymphoma lines. No mutations were found in any of the cases. We conclude that mutations in the BAD gene do not play a role in the pathogenesis of the major subtypes of human B-cell lymphomas.
Genetic instability leads to tumor heterogeneity, which in turn provides a source of cell variants responsible for drug resistance. However, the source of resistant cells during the process of acquired resistance is poorly understood. Our aim has been to characterize the mechanism by which acquired resistance to methotrexate emerges during the course of cancer cell treatment in vitro. We recently demonstrated that, in vitro, HT-29 colon cancer cells become transiently sensitive to methotrexate by depleting the extracellular milieu of survival factors; on the other hand, the cell population under treatment can reversibly adapt to grow below a critical cell density in the presence of the drug. Here, we show that this adapted cell population gives rise to permanent resistant populations through repeated cycles of cell death and growth. This increased cell turnover, but not merely cell proliferation, is required for the appearance of increasing degrees of stable resistance that are progressively selected by drug pressure. Such a process, taking place in multiple steps, is here designated "dynamic selection." The analysis of sensitive and resistant HT-29 cell populations revealed that methotrexate induces genomic instability--characterized by centrosome amplification and aberrant chromosome recombination--leading to a low-level amplification of the 5q chromosome arm as one of the earliest genetic events selected during treatment. Therefore, this model provides a mechanism by which a tumor cell population lacking resistant subpopulations before treatment is able to acquire the genetic changes required for stable drug resistance.
Our previous study demonstrate that vitamin D3 induces the binding of vitamin D3 receptor (VDR) to Sp1 transcription factor and stimulates p27Kip1 expression via the Sp1 consensus sequences in the promoter. Both VDR and Sp1 are transcriptional activators, it is unclear which protein functions as the transcription component of the VDR/Sp1 complex. To address this issue, we constructed the AF-2 deletion mutant of VDR and tested the effect of vitamin D3 on p27Kip1 expression. In consistent with our previous results, we found that expression of wild-type VDR in SW620 colon cancer cells, which expressed very low level of endogenous VDR, increased vitamin D3-stimulated p27Kip1 promoter activity and protein expression. On the contrary, expression of AF-2 deletion mutant had little effect. DNA affinity precipitation assay (DAPA) showed that both wild-type and deletion mutant of VDR bound to the DNA probe corresponding to the Sp1 binding site in the p27Kip1 promoter in a vitamin D3-dependent manner indicating deletion of AF-2 domain does not affect the interaction between VDR and Sp1. Chromatin immunoprecipitation (CHIP) assay also confirmed that VDR and its AF-2 deletion mutant bound to p27Kip1 promoter in vivo. We found that deletion of AF-2 domain abolished the interaction of coactivators SRC-1 and DRIP205 with VDR. Taken together, our results suggest that VDR functions as the transactivation component of the VDR/Sp1 complex to trigger gene expression.