Faculty of Biological Sciences

Dr Stephanie Wright

BA, Oxford; PhD, London.
Senior Lecturer
School of Biology

Background: Postdoctoral work with Prof. J. Michael Bishop, University of California San Francisco. Cancer Research Campaign Senior Research Fellow, Wellcome/CRC Institute of Cancer and Developmental Biology, Cambridge (1992-1995). Joined University of Leeds in 1995.

Contact:  Miall 8.17, +44(0) 113 34 33133, email address for  

You can read more about Dr Wright's interests here:
http://www.astbury.leeds.ac.uk/people/staff/staffpage.php?StaffID=SCW

Research Interests

Targeting transcription factor function in cancer therapy; the Myc/Max/Mxd transcription factor network in human cancer; BTB/POZ domain proteins; X-ray crystallography

The Myc/Max/Mxd transcription factor network in human cancer

The Myc/Max/Mxd transcription factor network plays a key role in the control of normal cellular proliferation and differentiation, and is deregulated in most human tumours.  c-Myc:Max heterodimers act as transcriptional activators that promote cell cycle progression, and many tumours are associated with overexpression of the c-Myc oncoprotein.  In contrast, Mxd:Max heterodimers are transcriptional repressors that antagonize c-Myc and are generally associated with growth arrest and differentiation.  Mnt is the most abundant Mxd family member and has been implicated as a tumour suppressor that is lost in several human malignancies.  We have shown that different Mxd family genes are expressed at specific stages of the cell cycle and differentiation, and have determined the mechanisms of this gene-specific regulation.  We are currently characterizing target genes that are bound by the Myc/Max/Mxd network in order to determine mechanisms of tumourigenesis.

The Miz1 transcription factor in cell differentiation and cancer

Miz1 is a BTB-domain transcription factor that activates genes involved in growth arrest, cellular differentiation and DNA damage responses.  Miz1 functions as a transcriptional activator by binding to initator DNA sequences of target genes, and the interaction of Miz1 with transcriptional repressors normally enables the suppression of Miz1 target genes at appropriate stages of cell proliferation, differentiation and development.  However, the aberrant overexpression of transcriptional repressors that interact with Miz1 leads to malignancy.  We have identified transcriptional repressors that interact with Miz1 and that are expressed at inappropriately high levels in human cancer (see also below).  We are currently determining the X-ray crystal structures of Miz1 interactions in order to design therapeutic inhibitors.

BTB/POZ domain proteins that regulate gene transcription and protein ubiquitination

The BTB (also known as POZ) domain is a protein-protein interaction domain that is found in transcription factors and in adaptor proteins of protein ubiquitination complexes.  The BTB domains of transcription factors serve to mediate dimerisation and the recruitment of transcriptional co-repressors, whereas the BTB domains of adaptor proteins interact with the core scaffold of protein ubiquitination complexes; other domains (such as MATH) of these adaptors interact with specific substrates for ubiquitination.  Some transcription factor BTB domains form specific biologically important heterodimeric interactions with each other.  Many BTB-domain proteins play roles in development, and several are implicated in specific human malignancies.  For example, the BTB-domain transcriptional repressors, BCL6 and Nac1, are overexpressed in diffuse large B-cell lymphoma and serous ovarian cancer respectively, and the BTB-domain adaptor, SPOP, is implicated in kidney cancer and prostate cancer.  High levels of Nac1 correlate with disease recurrence and resistance to chemotherapy.  We have determined the X-ray crystal structures of BTB-domain proteins implicated in specific malignancies; these include BTB-domain structures of BCL6, Miz1, Bach2 and Nac1, and also heterodimeric BTB domains of Miz1/BCL6 and Miz1/Nac1.  We have also shown that the adaptor protein, SPOP, forms high-order oligomers that enhance the efficiency of substrate ubiquitination, and have deduced the structural basis for this oligomerisation.  We are currently using these structures for the rational design of therapeutic inhibitors.

   Figure 1    X-ray crystal structure of the Nac1 BTB/POZ domain

 

Faculty Research and Innovation



Studentship information

Postgraduate studentship areas:

  • Applications are welcome from enthusiastic, committed students and postdocs to work on any of the above projects; please contact s.c.wright@leeds.ac.uk

See also:

Modules managed

BLGY2296 - Human Genetics
BLGY3152 - Advanced Topics in Human Genetics

Modules taught

BIOC2301 - Intermediate Integrated Biochemistry
BIOL5372M - Advanced Biomolecular Technologies
BLGY1303 - Tutorials for Biology and Genetics
BLGY2296 - Human Genetics
BLGY3021 - Research Project
BLGY3152 - Advanced Topics in Human Genetics
BLGY3291 - Comparative Genomics
BLGY3345 - Biology Integrated Research Projects

Centre membership: The Astbury Centre for Structural Molecular Biology

Group Leader Dr Stephanie Wright  (Senior Lecturer)

Targeting transcription factor function in cancer therapy; the Myc/Max/Mxd transcription factor network in human cancer; BTB/POZ domain proteins; X-ray crystallography  

Dr Mark Stead  (Visiting Researcher)

Dr Thomas Zacharchenko  (Research Fellow)


Stead MA, Wright SC Nac1 interacts with the POZ-domain transcription factor, Miz1 BIOSCIENCE REPORTS 34 227-235, 2014
DOI:10.1042/BSR20140049

Stead MA, Wright SC Structures of heterodimeric POZ domains of Miz1/BCL6 and Miz1/NAC1 Acta Crystallographica Section F:Structural Biology Communications 70 1591-1596, 2014
DOI:10.1107/S2053230X14023449
View abstract

van Geersdaele LK, Stead MA, Harrison CM, Carr SB, Close HJ, Rosbrook GO, Connell SD, Wright SC Structural basis of high-order oligomerization of the cullin-3 adaptor SPOP. Acta Crystallogr D Biol Crystallogr 69 1677-1684, 2013
DOI:10.1107/S0907444913012687
View abstract

Rosbrook GO, Stead MA, Carr SB, Wright SC The structure of the Bach2 POZ-domain dimer reveals an intersubunit disulfide bond. Acta Crystallogr D Biol Crystallogr 68 26-34, 2012
DOI:10.1107/S0907444911048335
View abstract

Stead MA, Carr SB, Wright SC Structure of the human Nac1 POZ domain ACTA CRYSTALLOGR F 65 445-449, 2009
DOI:10.1107/S1744309109012214

Stead MA, Rosbrook GO, Hadden JM, Trinh CH, Carr SB, Wright SC Structure of the wild-type human BCL6 POZ domain ACTA CRYSTALLOGR F 64 1101-1104, 2008
DOI:10.1107/S1744309108036063

Stead MA, Trinh CH, Garnett JA, Carr SB, Baron AJ, Edwards TA, Wright SC A beta-sheet interaction interface directs the tetramerisation of the Miz-1 POZ domain J MOL BIOL 373 820-826, 2007
DOI:10.1016/j.jmb.2007.08.026

Fox EJ, Stubbs SA, Kyaw Tun J, Leek JP, Markham AF, Wright SC PRELI (protein of relevant evolutionary and lymphoid interest) is located within an evolutionarily conserved gene cluster on chromosome 5q34–q35 and encodes a novel mitochondrial protein Biochemical Journal 378 817-825, 2003
DOI:10.1042/BJ20031504

Fox EJ, Wright SC The transcriptional repressor gene Mad3 is a novel target for regulation by E2F1 BIOCHEM J 370 307-313, 2003
DOI:10.1042/BJ20021583

Kime L, Wright SC Mad4 is regulated by a transcriptional repressor complex that contains Miz-1 and c-Myc BIOCHEM J 370 291-298, 2003
DOI:10.1042/BJ20021679

Fox EJ, Wright SC S-phase-specific expression of the Mad3 gene in proliferating and differentiating cells BIOCHEM J 359 361-367, 2001

Stoneley M, Spencer JP, Wright SC An internal ribosome entry segment in the 5 ' untranslated region of the mnt gene ONCOGENE 20 893-897, 2001

Fox E, Wright SC S-phase-specific expression of the Mad3 gene in proliferating and Biochemical Journal 359 361-367, 2001
DOI:10.1042/0264-6021:3590361

Wright SC, Luccarini C Effect of the position of TAR on transcriptional activation by HIV-1 Tat in vivo Journal of Molecular Biology 263 1-7, 1996

WRIGHT S, LU XB, PETERLIN BM HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT DIRECTS TRANSCRIPTION THROUGH ATTENUATION SITES WITHIN THE MOUSE C-MYC GENE JOURNAL OF MOLECULAR BIOLOGY 243 568-573, 1994
DOI:10.1016/0022-2836(94)90031-0

WRIGHT S REGULATION OF EUKARYOTIC GENE-EXPRESSION BY TRANSCRIPTIONAL ATTENUATION MOLECULAR BIOLOGY OF THE CELL 4 661-668, 1993

WRIGHT S, MIRELS LF, CALAYAG MCB, BISHOP JM PREMATURE TERMINATION OF TRANSCRIPTION FROM THE P1 PROMOTER OF THE MOUSE C-MYC GENE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 88 11383-11387, 1991
DOI:10.1073/pnas.88.24.11383

Wright S, Bishop JM DNA sequences that mediate attenuation of transcription from the mouse protooncogene myc Proceedings of the National Academy of Sciences of the United States of America 86 505-509, 1989
View abstract

Rosenthal A, Wright S, Quade K, Gallimore P, Cedart H, Grosveld F Increased MHC H-2K gene transcription in cultured mouse embryo cells after adenovirus infection Nature 315 579-581, 1985
DOI:10.1038/315579a0
View abstract

Taramelli R, Grosveld F, Wright SC The human beta-globin genes In Oxford Surveys on Eukaryotic Genes , 1985

Rosenthal A, Wright S, Cedar H, Flavell R, Grosveld F Regulated expression of an introduced MHC H-2K<sup>bm1</sup>gene in murine embryonal carcinoma cells Nature 310 415-418, 1984
DOI:10.1038/310415a0
View abstract

Wright S, Rosenthal A, Flavell R, Grosveld F DNA sequences required for regulated expression ofβ-globin genes in murine erythroleukemia cells Cell 38 265-273, 1984
DOI:10.1016/0092-8674(84)90548-8
View abstract

Grosveld F, Kioussis D, Busslinger M, Wright SC, Hurst J, Vanin E, Flavell R DNA methylation and globin gene expressions In Transfer and expression of eukaryotic genes , 1984

WRIGHT S, DEBOER E, ROSENTHAL A, FLAVELL RA, GROSVELD F DNA-SEQUENCES REQUIRED FOR REGULATED EXPRESSION OF BETA-GLOBIN GENES IN MURINE ERYTHROLEUKEMIA-CELLS PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES 307 271-282, 1984
DOI:10.1098/rstb.1984.0127

Wright S, Deboer E, Grosveld FG, Flavell RA Regulated expression of the humanβ-globin gene family in murine erythroleukaemia cells Nature 305 333-336, 1983
DOI:10.1038/305333a0
View abstract

BUSSLINGER M, DEBOER E, WRIGHT S, GROSVELD FG, FLAVELL RA THE SEQUENCE GGCMCGG IS RESISTANT TO MSPI CLEAVAGE NUCLEIC ACIDS RESEARCH 11 3559-3569, 1983
DOI:10.1093/nar/11.11.3559

WRIGHT CVE, WRIGHT SC, KNOWLAND J PARTIAL-PURIFICATION OF ESTRADIOL-RECEPTOR FROM XENOPUS-LAEVIS LIVER AND LEVELS OF RECEPTOR IN RELATION TO ESTRADIOL CONCENTRATION EMBO JOURNAL 2 973-977, 1983

Flavell R, Grosveld F, Grosveld G, Wright SC, Busslinger M, de Boer E, Kioussis D, Mellor A, Golden L, Weiss E, Hurst J, Bud H, Bullman H, Simpson E, James R, Townsend A, Taylor P, Schmidt W, Ferluga J, Leben L, Santamaria M, Atfield G, Festenstein H Structure and expression of globin and H-2 genes In Gene Regulation. UCLA Symposium on Molecular and Cellular Biology , 1982

Moschonas N, de Boer E, Grosveld FG, Dahl HHM, Wright S, Shewmaker CK, Flavell RA Structure and expression of a clonedβ°thalassaemic globin gene Nucleic Acids Research 9 4391-4402, 1981
DOI:10.1093/nar/9.17.4391
View abstract