School of Medicine

Dr David Greenhalgh

Dr David A Greenhalgh
  • Senior Lecturer (Clinical Specialties)
  • Associate Academic (Institute of Cancer Sciences)

telephone: 01413306914
email: David.Greenhalgh@glasgow.ac.uk


Analysis of the molecular mechanisms underlying cancer.

The development of cancer is a highly complex, multistage mechanism involving mutations in the genes that control cell growth and differentiation. My interests centre on exploiting the classic mouse model of multistage skin carcinogenesis to investigate mutations in oncogenes and tumour suppressor genes that initiate cancer; assess which gene combinations induced the promotion phase giving benign tumours and identify genes that achieve malignancy. In either tissue culture [i.e. living skin equivalents] or transgenic mouse skin, genetic engineering technologies coupled to topical steroid application enable us to induced mutations at specific times and mimic the acquisition of additional genetic insults that drives cancer development in humans. A recent highlight focused on investigation of ras and fos oncogene cooperation with PTEN tumour suppressor gene loss. The ras/PTEN cooperation model gave benign tumours but conversion to carcinoma involved consequences of PTEN loss not ras, an important result if ras was the therapeutic target. Further, fos/PTEN co-operation produced a “dead end” benign tumour [keratoacanthoma], due to re-expression of tumour suppressor genes p53 and p21, which prevented malignant conversion and thus identified compensatory anti-cancer surveillance mechanisms in benign tumours possibly amenable to therapeutic induction. Another arm studies melanoma, where we seek to understand the interactions between mutations in either melanocytes, keratinocytes or both that drive early disease. Ideally, once we identify the specific gene combinations implicated in this complex process, it may result in accurate models to aid in the design and testing of novel therapies.

Jump to: 2009 | 2008 | 2006 | 2005 | 2003
Number of items: 10.

2009

Greenhalgh, D., Yao, D. , Quinn, J. , and Macdonald, F. (2009) RasHa activation interdicts compensatory p53/p21WAF expression in Fos/PTENnull skin carcinogenesis via initial p53 loss but retention of p21WAF limits malignant progression. In: American Association for Cancer Research (AACR) 100th Annual Meeting, 18-22 April 2009, Denver, USA.

Macdonald, F., Yao, D. , Quinn, J. , and Greenhalgh, D. (2009) Compensatory p53/p21WAF-induced differentiation in Fos/PTENnull skin carcinogenesis is interdicted by RasHa activation but retention of p21WAF inhibits malignant progression. In: British Society for Investigative Dermatology (BSID) Annual Meeting, 30 March - 1 April 2009, Royal Agricultural College, Cirencester, UK.

2008

Yao, D., Alexander, C.L., Quinn, J., Chan, W-C., Wu, H., and Greenhalgh, D.A. (2008) Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity. Journal of Cell Science, 121 (10). pp. 1758-1769. ISSN 0021-9533 (doi:10.1242/jcs.021147)

Yao, D, Alexander, CL , Quinn, JA , Chan, WC, Wu, H, and Greenhalgh, DA (2008) Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21(WAF)-induced differentiation triggered by GSK3 beta inactivation and reduced AKT activity. Journal of Cell Science, 121 (10). pp. 1758-1769.

2006

Yao, D., Alexander, C.L., Quinn, J.A., Porter, M.J., Wu, H., and Greenhalgh, D.A. (2006) PTEN loss promotes rasHa-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via rasHa-independent pathways. Cancer Research, 66 (3). pp. 1302-1312. ISSN 0008-5472

Shaw, M., Yao, D. , Quinn, J.A., and Greenhalgh, D.A. (2006) Paradoxical maintenance of E-cadherin following inducible PTEN ablation in Ras or Fos-mediated skin carcinogenesis identifies sentinel mechanisms geared to combat PTEN dysfunction. In: British Society for Investigative Dermatology Annual Meeting, 10-12 April 2006, Manchester.

Yao, DG, Alexander, CL, Quinn, JA, Porter, NJ, Wu, H, and Greenhalgh, DA (2006) PTEN loss promotes ras(Ha)-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via PTEN-associated pathways. Cancer Research, 66 . pp. 1302-1312. (doi:10.1158/0008-5472.CAN-05-2341)

2005

Yao, D., Quinn, J.A., and Greenhalgh, D.A. (2005) Inducible cre-mediated N-ras activation and PTEN inactivation in transgenic mouse melanocytes requires keratinocyte hyperplasia to elicit a melanocyte pathology. In: Montagne Symposia, 2004 and 6th International Skin Cancer Conference, 2004, Oct 2004, Salishan Resort, Newport, Oregon, USA.

2003

Bakirtzis, G et al. (2003) Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. Human Molecular Genetics, 12 . pp. 1737-1744. (doi:10.1093/hmg/ddg183)

Bakirtzis, G., Jamieson, S. , Aasen, T., Bryson, S. , Forrow, S., Tetley, L. , Finbow, M. , Greenhalgh, D. , and Hodgins, M. (2003) The effects of a mutant connexin 26 on epidermal differentiation. Cell Communication and Adhesion, 10 (4-6). pp. 359-364. ISSN 1541-9061 (doi:10.1080/cac.10.4-6.359.364)

This list was generated on Sat May 26 21:40:43 2012 BST.
  • Analysis of tumour progression via inducible PTEN, p53 or p21 knockout.
    British Skin Foundation
    2011 - 2012
     
  • Analysis of tumour progression via inducible PTEN, p53 or p21 knockout
    British Skin Foundation
    2009 - 2010
     
  • Proof of Concept initiative: Replacing Animals with new tissue models for mechanism-based drug development in the post-genome era
    Scottish Enterprise
    2005 - 2006
     
  • Analysis of malignant conversion in multistage HK1. ras/fos transgenic mouse skin carcinogenesis via inductible, conditional PTEN knockout
    British Skin Foundation
    2005 - 2005
     
  • Analysis of adhesion receptor signalling deregulation in transgenic mouse skin cancer via inducible, keratinocyte-specific suppressor gene..
    Cancer Research Campaign
    2001 - 2006