Loss of scribble causes cell competition in mammalian epithelial cells.
Doctoral thesis, UCL (University College London).
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Cancer is a disease caused by transformation of cells by the activation or over-expression of oncogenes such as Ras and c-myc, and the loss of tumour suppressor genes such as E-cadherin and scribble. The initial stage of tumourigenesis is the transformation of a single cell in an otherwise normal epithelium. What occurs at this stage is largely unknown - do the transformed cells and normal cells co-exist or is there an antagonism between them? This thesis examines the fate of epithelial cells that lose the tumour suppressor scribble when in an otherwise normal epithelium. The fate of scribble knockout clones has been studied in Drosophila melanogaster larval imaginal discs. It has been observed that scribble knockout clones are removed from the larval tissues by c-Jun N-terminal kinase (JNK) dependent apoptosis. It is though that this is an innate tumour suppressive mechanism. It is therefore of great interest and importance to understand if a similar phenomenon can be seen in mammalian cells. Scribble knockdown Madin-Darby canine kidney (MDCK) epithelial cells die only when surrounded by normal MDCK cells. Dead scribble short-hairpin RNA (shRNA) cells are apically extruded from the epithelium after cell death and exhibit classical apoptotic markers such as cytoplasmic condensation, caspase 3 activation and DNA fragmentation. Extrusion of dead scribble knockout cells occurs after initiation of apoptosis as blocking myosin activation results in many dead scribble knockout cells staying in the epithelial monolayer. Prior to cell death they maintain normal cell-cell adhesion with their normal MDCK neighbours and activate the stress induced protein kinase p38, but not c-‐Jun N‐- terminal kinase (JNK).
|Title:||Loss of scribble causes cell competition in mammalian epithelial cells|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > MRC/UCL Lab for Molecular Cell Biology|
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