... understanding life in molecular detail

Dr Stephanie Wright

Cancer biology, eukaryotic gene regulation, protein ubiquitination, X-ray crystallography

We are interested in proteins that are implicated in human cancer. We use biochemical, biophysical and cell biology approaches to characterise protein interactions and molecular mechanisms, and determine detailed molecular structures using X-ray crystallography. Our ultimate aim is to use this information for the development of cancer therapeutics.

Current major projects include:
  • The Myc/Max/Mxd transcription factor network in human cancer
  • The Miz1 transcription factor in cell differentiation and cancer
  • BTB/POZ domain proteins
  • Targeting protein-protein interactions in cancer therapeutics

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 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.  We are currently determining the X-ray crystal structures of Miz1 interactions in order to design therapeutic inhibitors.

Figure 1   X-ray crystal structure of the Miz1 BTB/POZ domain

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

Detailed research programme                  Close ▲

Senior Lecturer in Biochemistry and Molecular Biology, Leeds
BA Biochemistry (Oxford) 1980, PhD (London) 1984

Postdoctoral Research Fellow (California San Francisco) 1985-1992
Cancer Research Campaign Senior Research Fellow (Cambridge) 1992-1995

Miall 8.17
School of Biology
0113 34 33133

Selected Publications

  1. Stead MA and Wright SC.
    Structures of heterodimeric POZ domains of Miz1/BCL6 and Miz1/NAC1
    Acta Crystallogr Sect F Struct Biol Cryst Commun. 2014 Dec 1;70(Pt 12):1591-6

  2. Stead MA and Wright SC.
    Nac1 interacts with the POZ-domain transcription factor, Miz1
    Bioscience Reports. 2014 Jun; e00110
    DOI: 10.1042/BSR20140049

  3. 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. 2013 Sep;69(Pt 9):1677-84.

  4. Rosbrook GO, Stead MA, Carr SB, Wright SC.
    The structure of the Bach2 POZ-domain dimer reveals an intersubunit disulphide bond.
    Acta Crystallogr D Biol Crystallogr. 2012 Jan;68(Pt 1):26-34.