Dr Shanie Budhram-Mahadeo
Transcriptional regulation of gene expression:
Regulation of gene expression by transcription factors (TFs) is pivotal for determining cell fate during development and normal homeostasis, and de-regulation of gene transcription contribute to many diseases. The homeodomain TFs, POU4F1/Brn-3a (Brn-3a) and related POU4F2/Brn-3b, (Brn-3b), are distinct but related regulators that share high homology in the DNA binding POU domain but differ considerably in other regions. As such, Brn-3a and Brn-3b bind to similar DNA sequences in the promoters of target genes but can give rise to diverse effects on gene expression/cell fate.
However, the effects of these transcription factors are highly dependent on the tissue of expression and growth conditions as well as co-expression with other regulators such as p53. For example, Brn-3a enhances neuronal differentiation by activating synaptic protein SNAP25, neurofilament (NFH); a-internexin etc. and survival by increasing anti-apoptotic Bcl-2 or BclXL whilst repressing p53 mediated pro-apoptotic target genes (Bax and Noxa). In contrast, Brn-3b drives proliferation by activating cell cycle proteins, cyclin D1 and CDK4 but if co-expressed with p53, brn-3b cooperates with p53 to enhance Bax expression and hence apoptosis.
These findings have demonstrated how co-expression of different TFs can influence cell fate. Furthermore the cooperation between Brn-3b and p53 to promote apoptosis may support a novel paradigm for understanding how cells respond to conflicting signals arising from co-expression of Brn-3b which normally stimulates cell proliferation, and p53, which drives cell cycle arrest. Given their complex effects on cell fate, it is necessary to analyse the effects of Brn-3a and Brn-3b in cell/tissue specific context and determine how co-expression with other cellular factors can affect gene expression and cell fate.
Although Brn-3a and Brn-3b have been studied extensively in neuronal cells and retinal ganglion cells, respectively, these TF are expressed in other tissues/system such as the heart and are deregulated in diseases such as cancers. Our primary research in MMBU has focused on studying how transcriptional regulators such as Brn-3a and Brn-3b act in different tissues under normal conditions and identify changes that may contribute to diseases.
Control of cell fate by regulating gene expression
Dynamic Loading of Metal-Ceramic Composites
Dr Richard Jenner
- Mehta G, Sharma V, Habtesion A, Balasubramaniyan V, Davies NA, Jalan R, Budhram-Mahadeo V, Mookerjee RP (2012). GENE TRANSFER OF DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 REDUCES PORTAL PRESSURE IN A RODENT MODEL OF CIRRHOSIS. GUT, 61, A123 - A123. doi:10.1136/gutjnl-2012-302514b.123
- Mehta G, Shah N, Sharma V, Habtesion A, Davies N, Jalan R, Budhram-Mahadeo VS, Mookerjee R (2012). Hepatic Dimethylarginine Dimethylaminohydrolase-1 (DDAH-1) is Decreased in Acute-on-Chronic Liver Failure due to Post-Transcriptional Regulation by an Altered MicroRNA Profile.
- Fujita R, Ounzain S, Wang AC, Heads RJ, Budhram-Mahadeo VS (2011). Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment.. Cell Stress Chaperones, 16(4), 427 - 439. doi:10.1007/s12192-011-0256-8
- Ounzain S, Bowen S, Patel C, Fujita R, Heads RJ, Budhram-Mahadeo VS (2011). Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERα and growth factors via MAPK pathway.. Breast Cancer Res, 13(1), R5 - . doi:10.1186/bcr2809
- Berwick DC, Diss JK, Budhram-Mahadeo VS, Latchman DS (2010). A simple technique for the prediction of interacting proteins reveals a direct Brn-3a-androgen receptor interaction.. J Biol Chem, 285(20), 15286 - 15295. doi:10.1074/jbc.M109.071456
- Budhram-Mahadeo V (2008). TRANSCRIPTIONAL REGULATOR, BRN-3B/POU4F2 AND ITS TARGET GENES IN CONTROLLING GROWTH AND BEHAVIOUR OF BREAST CANCER CELLS. ANTICANCER RES, 28(5C), 3224 - 3224.
- Budhram-Mahadeo VS, Irshad S, Bowen S, Lee SA, Samady L, Tonini GP, Latchman DS (2008). Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells. Oncogene, 27, 145 - 154.
- Hudson CD, Sayan AE, Melino G, Knight RA, Latchman DS, Budhram-Mahadeo V (2008). Brn-3a/POU4F1 interacts with and differentially affects p73-mediated transcription. Cell Death and Differentiation, 15(8), 1266 - 1278.
- Farooqui-Kabir SR, Diss JKJ, Henderson D, Marber MS, Latchman DS, Budhram-Mahadeo V, Heads RJ (2008). Cardiac expression of Brn-3a and Brn-3b POU transcription factors and regulation of Hsp27 gene expression. Cell Stress and Chaperones, 13(3), 297 - 312.
- Budhram-Mahadeo V (2006). Targeting Brn-3b in breast cancer therapy" Invited review to Expert Opinion on Therapeutic Targets. Expert Opinion on Therapeutic Targets, 10(1), 15 - 25.
- Ndisang D, Faulkes DJ, Gascoyne D, Lee SA, Ripley BJ, Sindos M, Singer A, Budhram-Mahadeo V, Cason J, Latchman DS (2006). Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a. Oncogene, 25(1), 51 - 60.
- Budhram-Mahadeo VS, Latchman DS (2006). Targeting Brn-3b in breast cancer therapy. Expert Opinion on Therapeutic Targets, 10(1), 15 - 25.
- Budhram-Mahadeo VS, Bowen S, Lee S, Perez-Sanchez C, Ensor E, Morris P, Latchman D (2006). Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by co-operating in transactivation of bax expression. Nucleic Acids Research, 34(22), 6640 - 6652.
- Chantelle Hudson GM, A Emre Sayan DSLAB-M, V (2006). Brn-3a Transcription Factor binds p73 to regulate survival and cell cycle arrest in neuronal cells. Molecular and Cellular Biology, , - .
- Samady L, Faulkes DJ, Budhram-Mahadeo V, Ndisang D, Potter E, Brabant G, Latchman DS (2006). The Brn-3b POU family transcription factor represses plakoglobin gene expression in human breast cancer cells. International Journal of Cancer, 118(4), 869 - 878.
- Diss JKJ, Faulkes DJ, Walker MM, Patel A, Foster CS, Budhram-Mahadeo V, Djamgoz MBA, Latchman DS (2006). Brn-3a neuronal transcription factor functional expression in human prostate cancer. Prostate Cancer and Prostatic Diseases, 9, 83 - 91.
- Diss JK, Faulkes DJ, Walker MM, Patel A, Foster CS, Budhram-Mahadeo V, Djamgoz MB, Latchman DS (2006). Brn-3a neuronal transcription factor functional expression in human prostate cancer.. Prostate Cancer Prostatic Dis, 9(1), 83 - 91. doi:10.1038/sj.pcan.4500837
- Lee SA, Ndisang D, Patel C, Dennis JH, Faulkes DJ, D'Arrigo C, Samady L, Farooqui-Kabir S, Heads RJ, Latchman DS, Budhram-Mahadeo VS (2005). Expression of the Brn-3b Transcription Factor Correlates with Expression of HSP-27 in Breast Cancer Biopsies and Is Required for Maximal Activation of the HSP-27 Promoter. Cancer Research, 65(8), 3072 - 3080.
- Diss JK, Faulkes DJ, Walker MM, Patel A, Foster CS, Budhram-Mahadeo V, Djamgoz MB, Latchman DS (2005). Brn-3a neuronal transcription factor functional expression in human prostate cancer. PROSTATE CANCER PROSTATIC DIS, , - .
- Samady LF, D J Budhram-Mahadeo VN, D Potter EB, G Latchman DS (2005). The Brn-3b POU family transcription factor represses plakoglobin gene expression in human breast cancer cells. International Journal of Cancer, , - .
- Lee SA, Budhram-Mahadeo VS (2005). Brn-3b transcription factor in breast tumourigenesis: regulation of genes associated with growth and migration of cancer cells. Breast Cancer Research, 7, S58 - S59.
- Samady L, Dennis J, Budhram-Mahadeo V, Latchman DS (2004). Activation of CDK4 gene expression in human breast cancer cells by the Brn-3b POU family transcription factor. Cancer biology and therapy, 3, 317 - 323.
- Irshad S, Pedley RB, Anderson J, Latchman DS, Budhram-Mahadeo V (2004). The Brn-3b transcription factor regulates the growth, behavior, and invasiveness of human neuroblastoma cells in vitro and in vivo. Journal of Biological Chemistry, 279(20), 21617 - 21627. doi:10.1074/jbc.M312506200
- Hudson CD, Morris PJ, Latchman DS, Budhram-Mahadeo VS (2004). Brn-3a transcription factor blocks p53 mediated expression of pro-apoptotic target genes, Noxa and Bax, in-vitro and in-vivo to determine cell fate. Journal of Biological Chemistry, , - .
- Hudson CD, Podesta J, Henderson D, Latchman DS, Budhram-Mahadeo V (2004). Coexpression of Brn-3a POU protein with p53 in a population of neuronal progenitor cells is associated with differentiation and protection against apoptosis. Journal of Neuroscience Research, 78(6), 803 - 814.
- Farooqui-Kabir SR, Budhram-Mahadeo V, Lewis H, Latchman DS, Marber MS, Heads RJ (2004). Regulation of Hsp27 expression and cell survival by the POU transcription factor Brn3a. CELL DEATH DIFFER, 11(11), 1242 - 1244.
- Budhram-Mahadeo V, Morris P, Ndisang D, Irshad S, Lozano G, Pedley B, Latchman DS (2002). The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells.. Neuroscience Letters, 334(1), 1 - 4.
- (2002). Functional interaction between Brn-3a and SRC-1 co-activates Brn-3a-mediated transactivation. Biochemical and Biophysical Research Communications, 294(2), 487 - 495.
- (2002). Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter. Nucleic Acids Research, 30(22), 4872 - 4880.
- Budhram-Mahadeo V, Morris PJ, Latchman DS (2002). The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1). Oncogene, 21(39), 6123 - 6131. doi:10.1038/sj.onc.1205842
- (2001). A minimal Bcl-x promoter is activated by Brn-3a and repressed by p53. Nucleic Acids Research, 29(22), 4530 - 4540.
- (2001). The closely related POU family transcription factors Brn-3a and Brn-3b are expressed in distinct cell types in the testis. The International Journal of Biochemistry and Cell Biology, 33(10), 1027 - 1039.
- Dennis JH, Budhram-Mahadeo V, Latchman DS (2001). The Brn-3b POU family transcription factor regulates the cellular growth, proliferation, and anchorage dependence of MCF7 human breast cancer cells. ONCOGENE, 20(36), 4961 - 4971.
- Ndisang D, Budhram-Mahadeo V, Pedley RBAL, D S (2001). The Brn-3a transcription factor plays a key role in regulating the growth of cervical cells in vivo.. Oncogene, 20, 4899 - 4903.
- Ndisang D, Budhram-Mahadeo V, Pedley B, Latchman DS (2001). The Brn-3a transcription factor plays a key role in regulating the growth of cervical cancer cells in vivo. ONCOGENE, 20(35), 4899 - 4903.
- Ndisang D, Budhram-Mahadeo V, Singer A, Latchman DS (2000). Widespread elevated expression of the human papillomavirus (HPV)-activating cellular transcription factor Brn-3a in the cervix of women with CIN3 (cervical intraepithelial neoplasia stage 3). Clinical Science, 98, 601 - 602.
- Budhram-Mahadeo VS, Morris PJ, Smith MD, Midgeley CA, Boxer LM, Latchman DS (1999). p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. Journal of Biological Chemistry, 274, 15237 - 15244.
- Ndisang D, Budhram-Mahadeo V, Latchman DS (1999). The Brn-3a transcription factor plays a critical role in regulating human papilloma virus gene expression and determining the growth characteristics of cervical cancer cells.. J Biol Chem, 274(40), 28521 - 28527.
- Budhram-Mahadeo VS, Ndisang D, Ward T, Weber BL, Latchman DS (1999). The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells. Oncogene, 18, 6684 - 6691.
- Latchman DS, Budhram-Mahadeo V, Parker M (1998). The POU domain factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an ERE. Molecular and Cellular Biology, 18, 1029 - 1041.
- Budhram-Mahadeo V, Parker M, Latchman DS (1998). POU transcription factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an estrogen response element.. Mol Cell Biol, 18(2), 1029 - 1041.
- Budhram-Mahadeo V, Parker M, Latchman DS (1997). The POU domain factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an ERE. Molecular And Cellular Biology, 18, 1029 - 1041.
- Budhram-Mahadeo V, Morris PJ, Lakin ND, Dawson SJ, Latchman DS (1996). The different activities of the two activation domains of the Brn-3a transcription factor are dependent on the context of the binding site.. J Biol Chem, 271(15), 9108 - 9113.
- Budhram-Mahadeo V, Lillycrop KA, Latchman DS (1995). The levels of the antagonistic POU family transcription factors Brn-3a and Brn-3b in neuronal cells are regulated in opposite directions by serum growth factors.. Neurosci Lett, 185(1), 48 - 51.
- Budhram-Mahadeo V, Morris PJ, Lakin ND, Theil T, Ching GY, Lillycrop KA, Möröy T, Liem RK, Latchman DS (1995). Activation of the alpha-internexin promoter by the Brn-3a transcription factor is dependent on the N-terminal region of the protein.. J Biol Chem, 270(6), 2853 - 2858.
- Budhram-Mahadeo V, Theil T, Morris PJ, Lillycrop KA, Moroy T, Latchman DS (1994). The DNA target site for the Brn-3 POU family transcription factors can confer responsiveness to cyclic AMP and removal of serum in neuronal cells.. Nucleic Acids Res, 22(15), 3092 - 3098.
- Budhram-Mahadeo V, Lillycrop KA, Latchman DS (1994). Cell cycle arrest and morphological differentiation can occur in the absence of apoptosis in a neuronal cell line.. Neurosci Lett, 165(1-2), 18 - 22.
- Lillycrop KA, Budrahan VS, Lakin ND, Terrenghi G, Wood JN, Polak JM, Latchman DS (1992). A novel POU family transcription factor is closely related to Brn-3 but has a distinct expression pattern in neuronal cells.. Nucleic Acids Res, 20(19), 5093 - 5096.
- Budhram-Mahadeo V, Ounzain S, Fujita R, Heads RJ (). POU4F2/Brn-3b transcription factor in cardiac hypertrophy.
- Budhram-Mahadeo V (). Do Brn’s rule the heart? Brn-3 TFs in cardiac development, defects/disease.
- Budhram-Mahadeo V, Ounzain S, Fujita R, Clark JE, Heads RJ (). Induction of Brn-3b/POU4F2 in cardiac myocytes by angiotensin II can affect the fate and survival depending on co-expression with 53.