Cellular senescence is an irreversible growth-arrested state seen in primary human cells after a finite number of cell divisions both in culture and <i>in vivo</i>. The escape from senescence to immortalisation is often thought to be a prerequisite for carcinogenesis. Many changes in senescent cells are consistent with changes in tissue and organ function with age. I used serial analysis of gene expression (SAGE) to analyse global gene expression profiles in senescent and early passage human foetal fibroblasts (hff). A total of over 20,000 SAGE tags were sequenced and characterised, corresponding to 2,675 unique transcripts. Relative to the early passage hff, transcripts which were found to be markedly increased in senescent hff included those encoding <i>p21<sup>WAF1</sup></i>, <i>Cyclin D1, </i>ferritin heavy chain, transforming growth factor-beta induced gene (<i>BIGH3</i>), skin collagenase and amyloid. Amongst them, genes such as skin collagenase and amyloid are known to be up-regulated in human ageing. Together with these known genes, a number of "unknown" genes were up-regulated. Seven differentially expressed genes, up-regulated in senescence (<i>BIGH3, </i>prion, dickkopf (Xenopus laevis) homolog 1 (<i>dkk1</i>), Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (<i>CITED2</i>), <i>Rap1a</i> and Cysteine knot superfamily 1, bone morphogenetic protein antagonist 1 and retinoic acid receptor, alpha (<i>RARA</i>)) were selected for validation with reverse transcriptase-polymerase chain reaction (RT-PCR). The roles of these genes are discussed in relation to cancer and neurodegenerative diseases. My study demonstrates that replicative senescence is a complex phenomenon involving genes from the wingless-type (Wnt), mitogen-activated protein (Map) kinase kinases extracellular signal-regulated (Erk) kinase, transforming growth factor beta signalling and epigenetic pathways. The challenges remaining now are to identify senescence-related tumour suppressor gene(s) and to elucidate further the biochemical pathways of senescence.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:251848 |
| Date | January 2002 |
| Creators | Seow, Choon Sheong |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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