Short nucleotide polymorphic insertions in the MCL-1 promoter affect gene expression

Saxena, Anurag; Moshynska, Oksana; Moshynskyy, Igor; Neuls, Evan D.; Qureshi, Tania; Bosch, Mark; Voralia, Michael; Bonham, Keith

doi:10.1016/j.canlet.2006.11.007

Cited by 8 publications

(8 citation statements)

References 56 publications

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“…The promoter with no À190 insertion (þ0) contains 5 (GGCCCC) repeats and 1 (GCTCA) motif, the þ6-promoter has an extra repeat and þ18-promoter has 2 extra repeats and 1 extra motif, which are typically binding motifs for Sp1 as confirmed in ChIP analysis by Saxena et al 17 Our EMSA assays, luciferase reporter gene assays in solid cancer cell lines in vitro, superimposed with measurement of mRNA and protein expression in lung cancer tissues, further illustrated that À190 insertional polymorphisms enhanced MCL1 promoter activity and resulted in heightened gene expression. These results are in line with observations in previous reports.…”

Section: Discussionmentioning

confidence: 82%

“…9,17 In hematopoietic and epithelial cell lines, 6-and 18-nt insertions have positive effect on transcriptional activity of MCL1 compared with the wild-type or with an experimentally created deletion. 17,22 However, controversial results between different studies also existed. Freeman et al 11 observed that insertional variants displayed decreased promoter activity.…”

Section: Discussionmentioning

confidence: 99%

“…Several follow-up studies, however, argued against these findings and confirmed that the sequence insertions are not somatic oncogenic mutations but common hereditary polymorphisms, and they were not associated with clinical outcome of leukemia. [10][11][12][13][14][15][16] Even though correlation between the MCL1 promoter insertion and gene expression in leukemia was subsequently validated by Saxena et al, 17 its functional significance and clinical implications in solid cancer are still completely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context‐dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Jiang

Wang

et al. 2011

Cancer

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BACKGROUND: Dysfunction of molecules that regulate both apoptosis and proliferation is involved in tumorigenesis. A common insertional polymorphism in promoter of MCL1, a member of BCL2 family gene with the dual regulatory functions, has been shown to be functional in leukemia, but its association with cancer predisposition and prognosis has not been well established. We hypothesized that MCL1 promoter variants may modify risk of solid cancer. METHODS: We genotyped À190 insertional polymorphism and 3 linked single nucleotide polymorphisms (SNPs) (À627A>C, À298G>C, and À235C>A) in 320 lung cancer patients and 362 controls, and analyzed their functional significance. RESULTS: We confirmed that these regulatory variants correlated with enhanced promoter activity and elevated expression of both mRNA and protein in solid cancer cells and tissues. We further demonstrated that heightened expression of MCL1 resulted in decreased proliferation ability of lung cancer cells. We found a reduced cancer risk (adjusted odds ratio

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context‐dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Jiang

Wang

et al. 2011

Cancer

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“…Survivin, a member of the inhibitor of apoptosis (IAP1) family proteins, and Myeloid cell leukaemia-1 (Mcl-1), a member of B-cell lymphoma-2 (Bcl-2) family proteins, are known as downstream proteins of Sp1 14,31) . Survivin is highly expressed in various types of cancer, but not in most normal differentiated tissues 32) .…”

Section: Discussionmentioning

confidence: 99%

“…This finding showed that Sp1 may be related with apoptosis by BA in MC-3 cells. Survivin and Myeloid cell leukemia-1 (Mcl-1) are downstream proteins of Sp1 14,15) . We investigated the effect of BA on survivin and Mcl-1 in MC-3 cells treated with BA for 24 hr.…”

Section: Ba Inhibits Anti-apoptotic Protein Sp1 and Its Downstream Prmentioning

confidence: 99%

Betulinic Acid Induces Apoptosis in Humam Mucoepidermoid Carcinoma Cells Through Regulating Specificity Protein 1 and Its Downstream Molecule, Survivin

Lee¹,

Jung²,

Yoo³

et al. 2013

Journal of Food Hygiene and Safety

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-High-grade mucoepidermoid carcinomas (MECs) have difficulty in cure and 5-year survival rate is quiet low. Therefore, we need new therapeutic agents and molecular targets. Betulinic acid (BA) is one of the materials which is easily found in the world and shows tumor-suppress effects in various tumor types. In addition, many kinds of normal tissues have a resistance to BA treatment. In this study, we investigated the anti-proliferative activity of BA and its molecular targets in MC-3 human MEC cells using western blot analysis and DAPI staining. BA inhibited cell viability and induced apoptosis in MC-3 cells. It affected Specificity protein 1 (Sp1) and its downstream molecule, survivin whereas it did not affect myeloid cell leukemia-1 (Mcl-1). Therefore, we suggest that BA can be a potential anti-cancer drug candidate regulating Sp 1 and survivin to exert apoptotic cell death.

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Human oral cancers have altered expression of Bcl‐2 family members and increased expression of the anti‐apoptotic splice variant of Mcl‐1

Mallick

Patil²,

Gyanchandani

et al. 2008

The Journal of Pathology

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Expression of Bcl-2 family proteins in tumours can modulate apoptosis, influencing tumour behaviour and treatment. To investigate their role in oral tumourigenesis, nine Bcl-2 family transcripts were examined in three oral cell lines and 25 oral tumours, using ribonuclease protection assay. Since Mcl-1 mRNA was elevated in these samples, Mcl-1 splice variants were assessed by RT-PCR and Mcl-1 protein was studied in normal, premalignant and malignant oral tissues and cell lines, by immunohistochemistry and/or immunoblotting. The cell lines exhibited significantly higher levels of 7/9 Bcl-2 family transcripts as compared to those in normal tongue, and significantly higher (p=0.030, p=0.004) anti-apoptotic versus pro-apoptotic transcripts. Elevated Mcl-1 mRNA was observed in 11/25 (44%) tumours as compared to normal tissues with a five- to ten-fold higher expression of full-length anti-apoptotic Mcl-1 transcript versus the pro-apoptotic short isoform. Strong cytoplasmic Mcl-1 immunoreactivity was detected predominantly in differentiated epithelia in 27/33 (82%) oral tumours, 18/20 (90%) leukoplakia, 25/30 (83%) submucous fibrosis and 3/3 oral cell lines, with weak staining in 8/15 (53%) normal mucosa samples. Mcl-1 positivity in malignant and premalignant tissues was comparable but significantly higher (p<0.01) than that in normal mucosa. The expression of bcl-2 family genes, including Mcl-1 in tumours, did not correlate significantly with clinicopathological parameters. This is the first report delineating the in vivo expression patterns of Mcl-1 protein and Mcl-1 transcripts in oral cancers and premalignant lesions. The observed imbalance between expression of anti-apoptotic and pro-apoptotic Bcl-2 family genes may promote survival in the oral cell lines. Since the majority of oral tumours associated with tobacco-chewing evolve from premalignant lesions, the sustained expression of full-length anti-apoptotic Mcl-1 protein in these tissues suggests an important role for Mcl-1, early in oral cancer pathogenesis in protecting cells from apoptosis via neutralization of pro-apoptotic members and could be a potential therapeutic target for oral cancers.

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Short nucleotide polymorphic insertions in the MCL-1 promoter affect gene expression

Cited by 8 publications

References 56 publications

Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context‐dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context‐dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Betulinic Acid Induces Apoptosis in Humam Mucoepidermoid Carcinoma Cells Through Regulating Specificity Protein 1 and Its Downstream Molecule, Survivin

Human oral cancers have altered expression of Bcl‐2 family members and increased expression of the anti‐apoptotic splice variant of Mcl‐1

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