Imperial College London

ProfessorSimakAli

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

154 results found

BULUWELA LAKJAYA, HOLMES DAVID, KAMALATI TAHEREH, WAXMAN JONATHAN, ALI SIMAKet al., 2002, CONTROL OF GENE EXPRESSION

A method of suppressing the expression of a selected endogenous gene in a eukaryotic cell the method comprising introducing into the cell (a) a polypeptide comprising a nucleic acid binding portion which binds to a site at or associated with the selected gene and a modifying portion which comprises a polypeptide or peptidomimetic which is capable of modulating covalent modification of nucleic acid or chromatin, for example a chromatin inactivation portion, or (b) a polynucleotide encoding said polypeptide. The binding of the molecule to nucleic acid may be modulated by a ligand and the molecule may comprise a ligand binding portion. The nucleic acid binding portion may be a nucleic acid binding portion of a nuclear receptor DNA binding protein.

Journal article

Ali S, Coombes RC, 2002, Endocrine-responsive breast cancer and strategies for combating resistance, NATURE REVIEWS CANCER, Vol: 2, Pages: 101-+, ISSN: 1474-175X

Journal article

Ali S, Coombes RC, 2002, Endocrine responsive breast cancer and strategies for combating resistance, Nat Rev Cancer, Vol: 2, Pages: 101-112, ISSN: 1474-175X

Journal article

Vigushin DM, Ali S, Pace PE, Mirsaidi N, Ito K, Adcock I, Coombes RCet al., 2001, Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo, CLINICAL CANCER RESEARCH, Vol: 7, Pages: 971-976, ISSN: 1078-0432

Journal article

Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri Het al., 2001, Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance., J Biol Chem, Vol: 276, Pages: 9817-9824, ISSN: 0021-9258

Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERalpha. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERalpha in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression.

Journal article

Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri Het al., 2001, Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha - A new model for anti-estrogen resistance, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 276, Pages: 9817-9824, ISSN: 0021-9258

Journal article

Thomson SD, Ali S, Pickles L, Taylor J, Pace PE, Lymboura M, Shousha S, Coombes RCet al., 2001, Analysis of estrogen-responsive finger protein expression in benign and malignant human breast, INTERNATIONAL JOURNAL OF CANCER, Vol: 91, Pages: 152-158, ISSN: 0020-7136

Journal article

, 2001, Control of gene expression, WO 01/02019

Patent

, 2001, Control of gene expression, WO 01/02019

Patent

Liu D, Buluwela L, All S, Thomson S, Gomm JJ, Coombes RCet al., 2001, Retroviral infection of the FGF2 gene into MCF-7 cells induces branching morphogenesis, retards cell growth and suppresses tumorigenicity in nude mice, EUROPEAN JOURNAL OF CANCER, Vol: 37, Pages: 268-280, ISSN: 0959-8049

Journal article

Ali S, Coombes RC, 2000, Estrogen receptor alpha in human breast cancer: Occurrence and significance, JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA, Vol: 5, Pages: 271-281, ISSN: 1083-3021

Journal article

Chen DS, Riedl T, Washbrook E, Pace PE, Coombes RC, Egly JM, Ali Set al., 2000, Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7, MOLECULAR CELL, Vol: 6, Pages: 127-137, ISSN: 1097-2765

Journal article

BULUWELA LAKJAYA, ALI SIMAK, 2000, CONTROL OF GENE EXPRESSION

A method of suppressing the expression of a selected gene in a eukaryotic cell the method comprising introducing into the cell (a) a polypeptide comprising a DNA binding portion which binds to a site at or associated with the selected gene which site is present in a plant or animal genome and a chromatin inactivation portion, or (b) a polynucleotide encoding said polypeptide.

Journal article

BULUWELA LAKJAYA, ALI SIMAK, 2000, Control of gene expression

A method of suppressing the expression of a selected gene in a eukaryotic cell the method comprising introducing into the cell (a) a polypeptide comprising a DNA binding portion which binds to a site at or associated with the selected gene which site is present in a plant r animal genome and a chromatin inactivation portion, or (b) a polynucleotide encoding said polypeptide.

Journal article

ALI Simak Imperial College School of Med, BULUWELA Lakjaya Imperial College School of Med, 2000, CONTROL OF GENE EXPRESSION

A method of suppressing the expression of a selected gene in a eukaryotic cell the method comprising introducing into the cell (a) a polypeptide comprising a DNA binding portion which binds to a site at or associated with the selected gene which site is present in a plant or animal genome and a chromatin inactivation portion, or (b) a polynucleotide encoding said polypeptide.

Journal article

Chen DS, Pace PE, Coombes RC, Ali Set al., 1999, Phosphorylation of human estrogen receptor alpha by protein kinase A regulates dimerization, MOLECULAR AND CELLULAR BIOLOGY, Vol: 19, Pages: 1002-1015, ISSN: 0270-7306

Journal article

Pedeutour F, Quade BJ, Weremowicz S, Dal Cin P, Ali S, Morton CCet al., 1998, Localization and expression of the human estrogen receptor beta gene in uterine leiomyomata, Genes Chromosomes and Cancer, Vol: 23, Pages: 361-366, ISSN: 1045-2257

Estrogens have an important function in the natural history of uterine leiomyomata. The human estrogen receptor beta gene (ESR2) has been identified recently and mapped to 14q22-24, a region frequently rearranged in uterine leiomyomata and other benign tumors, including pulmonary chondroid hamartomas and endometrial polyps. Using fluorescence in situ hybridization and radiation hybrid mapping, we map ESR2 within 14q23-24.1 to a region approximately 2 Mb centromeric to the t(12;14) breakpoint in uterine leiomyomata, between markers DI4S63 and WI-7536. Two YAC clones, 948B6 and 741H4, contain ESR2. Using RT-PCR, we show that ESR2 is expressed in uterine leiomyomata and pulmonary chondroid hamartomas as well as in normal myometrium. Lack of a direct relationship between rearrangement of 14q23-24 and ESR2 expression suggests that ESR2 is not involved with HMGIC or HMGIY in t(12;14) or t(6;14). However, because of its relatively close physical distance from the characteristic site of rearrangements in 14q23-24, a role for ESR2 in the pathobiology of these tumors warrants future consideration.

Journal article

Pedeutour F, Quade BJ, Weremowicz S, Dal Cin P, Ali S, Morton CCet al., 1998, Localization and expression of the human estrogen receptor beta gene in uterine leiomyomata, GENES CHROMOSOMES & CANCER, Vol: 23, Pages: 361-366, ISSN: 1045-2257

Journal article

Taylor J, Lymboura M, Pace PE, A'Hern RP, Desai AJ, Shousha S, Coombes RC, Ali Set al., 1998, An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers, INTERNATIONAL JOURNAL OF CANCER, Vol: 79, Pages: 334-342, ISSN: 0020-7136

Journal article

Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali Set al., 1997, Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 272, Pages: 25832-25838, ISSN: 0021-9258

Journal article

Desai AJ, Luqmani YA, Walters JE, Coope RC, Dagg B, Gomm JJ, Pace PE, Rees CN, Thirunavukkarasu V, Shousha S, Groome NP, Coombes R, Ali Set al., 1997, Presence of exon 5-deleted oestrogen receptor in human breast cancer: Functional analysis and clinical significance, British Journal of Cancer, Vol: 75, Pages: 1173-1184, ISSN: 1532-1827

A variant form of the human oestrogen receptor (ER) mRNA lacking sequences encoded within exon 5 has been described (Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malloy BW, McGuire WL 1991, Cancer Res 51: 105-109). We have examined the expression of the exon 5-deleted ER (HE delta5) mRNA variant in breast biopsies using reverse transcriptase polymerase chain reaction (RT - PCR). HE delta5 mRNA was present in only 13% of non-malignant breast tissues compared with 32% of carcinomas (95% CI, P=0.05). Presence of the HE delta5 mRNA was associated with the presence of immunohistochemically detected ER (P=0.015) and progesterone receptor (PR) (P=0.02). There was a positive correlation between the presence of HE delta5 and disease-free survival (P=0.05), suggesting that the presence of HE delta5 may be an indicator of better prognosis. We have raised a monoclonal antibody specific to the C-terminal amino acids of HE delta5. This antibody recognized the variant but not the wild-type ER protein. We show that HE delta5 protein is present in breast cancer using immunohistochemical techniques. We also analysed trans-activation by HE delta5 in mammalian cells and showed that, in MCF-7 cells, HE delta5 competes with wild-type ER to inhibit ERE-dependent trans-activation. Our results indicate that this variant is unlikely to be responsible for endocrine resistance of breast cancer, but its presence at both the mRNA and protein level suggest that it may, nevertheless, be involved in regulating the expression of oestrogen-responsive genes in breast cancer.

Journal article

Metzger D, Berry M, Ali S, Chambon Pet al., 1995, Effect of antagonists on DNA binding properties of the human estrogen receptor in vitro and in vivo., Mol Endocrinol, Vol: 9, Pages: 579-591, ISSN: 0888-8809

Functional analyses, performed with the estrogen receptor (ER) isolated from different sources or produced with various expression systems, led to contradictory results concerning the role of estrogen (E2) and antiestrogens in ER DNA binding. Here we report the DNA-binding properties of the human ER and show that the wild type ER (HEG0) binds in vitro to an estrogen response element (ERE) as a dimer, irrespective of the presence or absence of estrogen. We also show that the two antihormones, 4-hydroxytamoxifen (OHT, a partial ER agonist) and ICI 164,384 (a pure antagonist) do not impair HEG0 dimerization and DNA binding in vitro. Exposure of HEG0 to elevated temperature (37 C) in vitro results in a much faster reduction of its binding capacity to an ERE in the absence of ligand or in the presence of ICI 164,384 than in the presence of either E2 or OHT. The Gly to Val mutation at amino acid 400 present in the human ER that we initially cloned (HE0), is responsible for an even faster heat inactivation of unliganded receptor compared with HEG0 and largely accounts for the previously observed in vitro ligand-dependent DNA binding of ER. We also show that, as previously observed for OHT, ICI 164,384 does not prevent ER binding to an ERE in vivo, even though ICI 164,384 acts as a pure antagonist for transcriptional activation by ER. We discuss these results in the context of a ligand-dependent interaction between the C-terminal region E, which contains the ligand-binding domain, and the N-terminal A/B region, which contains the activation function AF-1.

Journal article

Metzger D, Ali S, Bornert JM, Chambon Pet al., 1995, Characterization of the amino-terminal transcriptional activation function of the human estrogen receptor in animal and yeast cells., J Biol Chem, Vol: 270, Pages: 9535-9542, ISSN: 0021-9258

We have previously reported that the transcriptional activation function AF-1, located in the A/B region of the human estrogen receptor, exhibits cell-type and promoter context specificity in both animal cells and yeast. To further characterize AF-1, we have constructed a number of deletion mutants spanning the A/B region in the context of either the whole human estrogen receptor or the A/B region linked to the GAL4 DNA binding domain, and tested their transcriptional activity in chicken embryo fibroblasts and in yeast cells, two cell types in which AF-1 efficiently activates transcription on its own. Additionally, we utilized HeLa cells in which AF-1 is poorly active but can synergize with the transcriptional activation function AF-2 located in the hormone binding domain. We show that in animal cells the "independent" activity of AF-1 is embodied in a rather hydrophobic proline-rich 99-amino acid activating domain (amino acids 51-149), whereas amino acids 51-93 and 102-149 can independently synergize with AF-2. Interestingly, in yeast, three discrete activating domains (amino acids 1-62, 80-113, and 118-149) are almost as active on their own as the whole A/B region, indicating that multiple activating domains can operate independently in yeast. Our study also demonstrates that, within the context of the whole human estrogen receptor, the same AF-1 activating domains are "induced" by either estradiol or 4-hydroxytamoxifen.

Journal article

Ali S, Lutz Y, Bellocq JP, Chenard-Neu MP, Rouyer N, Metzger Det al., 1993, Production and characterization of monoclonal antibodies recognising defined regions of the human oestrogen receptor., Hybridoma, Vol: 12, Pages: 391-405, ISSN: 0272-457X

Mouse monoclonal antibodies were raised against the N-terminal (amino acids 151-165) and the very C-terminal (amino acids 578-595) regions of the human oestrogen receptor (hER). These antibodies recognise the hER by enzyme-linked immunosorbent assay, immunocytochemistry, immunoblotting, immunoprecipitation and gel retardation assays. The presence of hER is used prognostically in human breast cancer. We have tested the reactivity of our monoclonal antibodies on breast cancer sections, comparing with the commonly used Abbott rat monoclonal antibody H222. These studies show that the two monoclonal antibodies described here are highly versatile and will be useful tools for in vivo and in vitro studies of hER function. Furthermore, we show that the corresponding epitopes can be used as molecular "tags" for heterologous proteins and offer a powerful means of purifying and/or characterizing over-produced fusion proteins containing these regions.

Journal article

Ali S, Metzger D, Bornert JM, Chambon Pet al., 1993, Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region., EMBO J, Vol: 12, Pages: 1153-1160, ISSN: 0261-4189

Using a transient co-transfection system, we show that the human oestrogen receptor (hER) becomes phosphorylated in the presence of oestradiol (E2) as well as in the presence of the anti-oestrogens 4-hydroxy-tamoxifen (OHT) and ICI 164, 384 (ICI), although at lower efficiencies than with E2. There are multiple sites of phosphorylation in hER; using deletion and point mutants one of these sites has been mapped in the N-terminal A/B region at serine 118. Mutation of this serine to alanine caused, in a number of cell types, a significant reduction in transcriptional activation by hER from reporter genes containing an oestrogen response element (ERE), but did not affect the DNA binding properties or nuclear localization of hER. Thus phosphorylation of serine 118 is important for the action of the transcription activation function 1 (AF-1) located in the A/B region of the oestrogen receptor.

Journal article

Brou C, Wu J, Ali S, Scheer E, Lang C, Davidson I, Chambon P, Tora Let al., 1993, Different TBP-associated factors are required for mediating the stimulation of transcription in vitro by the acidic transactivator GAL-VP16 and the two nonacidic activation functions of the estrogen receptor., Nucleic Acids Res, Vol: 21, Pages: 5-12, ISSN: 0305-1048

The estrogen receptor (ER) contains two nonacidic transcriptional activation functions, AF-1 and AF-2 (formerly TAF-1 and TAF-2). In this study we show that AF-1 and AF-2 are able to stimulate transcription in vitro in a HeLa cell system when fused to the DNA binding domain of the yeast activator GAL4. We also demonstrate that a factor(s) required for the function of the ER AFs is chromatographically separable from a factor(s) necessary for the activity of the acidic activation domain of VP16. Moreover, immunoprecipitation experiments using a monoclonal antibody directed against the TATA box binding protein (TBP) indicate, that these different factors are associated with TBP in distinct TFIID complexes.

Journal article

Rochette-Egly C, Gaub MP, Lutz Y, Ali S, Scheuer I, Chambon Pet al., 1992, Retinoic acid receptor-beta: immunodetection and phosphorylation on tyrosine residues., Mol Endocrinol, Vol: 6, Pages: 2197-2209, ISSN: 0888-8809

Polyclonal (RP) and monoclonal (Ab) antibodies were raised against synthetic peptides (or fusion proteins) corresponding to amino acid sequences unique to human and mouse retinoic acid receptor-beta (RAR beta) isoforms. Antibodies directed against the A2 region [Ab6 beta 2(A2), Ab7 beta 2(A2), and RP beta 2(A2)], the D2 region [RP beta(D2)], or the F region [Ab8 beta(F)2, RP beta(F)1, and RP beta(F)2] were selected. The monoclonal and polyclonal antibodies directed against the D2 and F regions specifically immunoprecipitated and recognized by Western blotting all human and mouse RAR beta isoforms (mRAR beta 1, -beta 2, -beta 3, and -beta 4), produced in COS-1 cells transfected with expression vectors containing the corresponding RAR beta cDNA. Furthermore, in gel retardation assays, the monoclonal antibodies supershifted RAR beta protein-RA response element oligonucleotide complexes. Antibodies directed against the A2 region were specific for the RAR beta 2 isoform. The above antibodies allowed us to detect the presence of mRAR beta 2 proteins in mouse embryos and to show that their presence in embryonal carcinoma cells (F9 and P19 cell lines) is dependent upon RA treatment. The antibodies were also used to demonstrate that RAR beta proteins produced by transfection in COS-1 cells are phosphorylated. RAR beta 2 phosphorylation was not affected by RA treatment, whereas the phosphorylation of RAR beta 1 and RAR beta 3 isoforms was greatly enhanced by RA. We also show that, in contrast to RAR alpha 1 and RAR gamma 1, RAR beta 2 proteins contain phosphotyrosine residues and are only weakly phosphorylated in vitro by cAMP-dependent protein kinase. These results support our previous proposal that the various receptors have distinct functions in the RA-signaling pathway.

Journal article

Gaub MP, Rochette-Egly C, Lutz Y, Ali S, Matthes H, Scheuer I, Chambon Pet al., 1992, Immunodetection of multiple species of retinoic acid receptor alpha: evidence for phosphorylation., Exp Cell Res, Vol: 201, Pages: 335-346, ISSN: 0014-4827

Polyclonal and monoclonal antibodies were raised against synthetic peptides (or fusion protein) corresponding to cDNA-deduced amino acid sequences unique to the human and mouse retinoic acid (RA) receptor alpha 1 (hRAR-alpha 1 and mRAR-alpha 1, respectively). Two rabbit polyclonal antibodies directed against either the F region fused to DHFR [RP alpha (F)] or the D2 region [RP alpha (D2)] were selected. Using either immunocytochemistry, Western blotting analysis, or immunoprecipitation, they were found to be specific for human and mouse RAR-alpha 1 proteins produced by COS-1 cells transiently transfected with vectors expressing the RAR-alpha 1 cDNA. Three mouse monoclonal antibodies directed against either the F region [(Ab9 alpha (F) and Ab12 alpha (F)] or the A1 region [Ab10 alpha 1(A1)] recognized transiently expressed human and mouse RAR-alpha 1 proteins, when either immunocytochemistry or immunoprecipitation was used. In addition, Ab9 alpha (F) and Ab12 alpha (F), but not Ab10 alpha 1(A1), revealed the RAR-alpha 1 proteins by Western blotting analysis. Ab9 alpha (F) was also able to "supershift" RAR-alpha 1 protein-RARE oligonucleotide probe complexes in gel retardation assays. All these antibodies recognized also the transiently expressed mRAR-alpha 2 isoform, with the exception of Ab10 alpha 1 (A1), which is specific for the A1 region of RAR-alpha 1. These antibodies have enabled us to detect the presence of mRAR-alpha as multiple species in mouse embryo and adult tissue extracts as well as in embryonal carcinoma (EC) cells. Moreover, we found that one of these species (51 kDa) was phosphorylated in EC cells. This phosphorylation was not affected by RA treatment, but appeared to be dependent on the differentiation state of the EC cells.

Journal article

Harris S, McClenaghan M, Simons JP, Ali S, Clark AJet al., 1991, Developmental regulation of the sheep beta-lactoglobulin gene in the mammary gland of transgenic mice., Dev Genet, Vol: 12, Pages: 299-307, ISSN: 0192-253X

beta-Lactoglobulin (BLG) is the most abundant whey protein in sheep milk but it is not present in mouse milk. We have previously shown that transgenic mice carrying the BLG gene express it specifically in the mammary gland and secrete BLG into milk at high concentrations. Here we demonstrate that BLG transcription is correctly initiated in mice and that BLG synthesis is restricted to the secretory epithelial cells of the mammary gland. We have also determined the temporal pattern of milk protein gene expression and find that the BLG transgene is regulated coordinately with mouse beta-casein and that the patterns of regulation of BLG in mouse and sheep share some similarities.

Journal article

ALI S, MCCLENAGHAN M, SIMONS JP, CLARK AJet al., 1990, CHARACTERIZATION OF THE ALLELES ENCODING OVINE BETA-LACTOGLOBULIN-A AND BETA-LACTOGLOBULIN-B, GENE, Vol: 91, Pages: 201-207, ISSN: 0378-1119

Journal article

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