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
BLGY2100 - Enhanced Study Skills for Biologists
BLGY2296 - Human Genetics
BLGY3152 - Advanced Topics in Human Genetics
BLGY3291 - Comparative Genomics

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)