Drayton, Sarah; (2003) Neoplastic transformation of p16INK4a - deficient human fibroblast by co-operating cellular oncogenes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A common defensive mechanism used by proliferating cells in response to potentially damaging signals is the induction of cell cycle arrest. The upregulation of the cell cycle inhibitor, p16INK4a, causes arrest in response to a variety of cellular insults such as environmental stress, oncogenic signalling and telomere loss. Remarkably, the DNA locus on which the INK4a gene is found, CDKN2A, encodes two structurally distinct proteins that are expressed in response to inappropriate proliferative signals, and activate pivotal cell cycle control and tumour suppressor pathways. Thus, p16INK4a prevents the phosphorylation and functional inactivation of the retinoblastoma protein (Rb) by cyclin dependent kinases, whereas p14ARF prevents the Mdm2-mediated ubiquitination and degradation of p53. Therefore, this single genomic locus has the capacity to modulate signals to both Rb and p53 - the executors of two pivotal checkpoints in the cell division cycle. To gain further insight into the roles of INK4a and ARF, the behaviour of primary human dermal fibroblasts from rare, melanoma-prone individuals who have inherited germline mutations in both alleles of pihas been investigated. These cells are operationally deficient for p16INK4a but functional for p14ARF. Work presented in this thesis shows that, when immortalized by telomerase, they are resistant to the arrest induced by expression of either ectopic Ras or Myc in wild-type cells, and are able to grow as anchorage-independent colonies in soft agar. However, they do not grow as tumours in nude mice. Cells expressing both Myc and Ras form large colonies and are able to grow as tumours in nude mice. Due to the low penetrance and long latency of these tumours, they have been analysed for additional acquired alterations that may be required for tumorigenesis. Thus, an attempt has been made to establish the minimum number of alterations to cellular genes required to convert a primary human fibroblast into a tumour cell.

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