The apoptotic function of p53 is specifically regulated by iASPP and ASPP2 and their additional modulation of p63, a key regulator of squamous epithelial homeostasis, has been demonstrated in mice. In this study the role of iASPP and ASPP2 in human carcinomas was explored with a particular focus on the development of squamous cell carcinomas. The predominant expression of cytoplasmic ASPP2 is seen in the superficial, terminally differentiated cell layers of normal squamous epithelia and its loss is documented in areas of dysplasia and in squamous cell carcinomas. In addition the absence of nuclear ASPP2 in association with human papillomavirus infection suggests it could be a novel viral target. Furthermore in a novel mouse model of lung tumourigenesis, the somatic deletion of ASPP2 is shown to promote the over expression of markers associated with specific lung progenitor cells and to be associated with the development of non small cell lung carcinomas. Conversely nuclear iASPP expression is seen in p63 expressing, replication competent, basal and parabasal squamous epithelial cells and is increased in areas of dysplasia and in squamous cell carcinomas. Moreover the combination of nuclear iASPP, p63 and loss of ASPP2 expression is seen to be associated with cell survival and characterises the invasive edges of lingual squamous cell carcinomas. The novel interaction of iASPP with ERα is also demonstrated together with the negative impact of nuclear iASPP on ER positive breast cancer survival, potentially identifying iASPP as a novel player in estrogen signalling and an important factor in breast tumourigenesis. Together the data presented here provide significant corroborative evidence implicating ASPP2 and iASPP in tumourigenesis. Specifically ASPP2 is shown to promote cellular differentiation and inhibit the expansion of proliferative populations whereas nuclear iASPP promotes the survival of potentially neoplastic clones. It is likely that the balance of these proteins is a key factor in determining individual cell fate decisions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:629543 |
| Date | January 2014 |
| Creators | Salter, Victoria Lesley Jutta |
| Contributors | Lu, Xin |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:7d5cbb11-3964-4933-9947-b0e5514ae7cb |
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