A Genome-wide Human ORF Gain-of-function Screen to Identify Genes that can Bypass p16INK4a-mediated Cellular Senescence

Lee, W. J., Skalamera, D., Dahmer, M., Shakhbazov, K., Purdon, A., Wilson, B., Ranall, M, Pinder, A., Pavey, S., Gonda, T. and Gabrielli, B. (2012). A Genome-wide Human ORF Gain-of-function Screen to Identify Genes that can Bypass p16INK4a-mediated Cellular Senescence. In: 6th Australian High Content Screening Group Meeting, Melbourne, Australia, (). 13th July 2012.

Author Lee, W. J.
Skalamera, D.
Dahmer, M.
Shakhbazov, K.
Purdon, A.
Wilson, B.
Ranall, M
Pinder, A.
Pavey, S.
Gonda, T.
Gabrielli, B.
Title of paper A Genome-wide Human ORF Gain-of-function Screen to Identify Genes that can Bypass p16INK4a-mediated Cellular Senescence
Conference name 6th Australian High Content Screening Group Meeting
Conference location Melbourne, Australia
Conference dates 13th July 2012
Publication Year 2012
Year available 2012
Sub-type Other
Collection year 2013
Language eng
Formatted Abstract/Summary
Cellular senescence is a genuine tumour suppressor mechanism. It can be induced by ionising radiation, activated oncogenes and by the p16INK4a tumour suppressor gene, commonly known as p16, which is frequently mutated, deleted or silenced in melanoma and other cancers. Human naevi or moles represent a unique system to study senescence and early stage tumour initiation in a non-epithelial cell type. The expression of high p16 levels is commonly observed in naevi along with other features of senescence, such as proliferative arrest. However, early stage primary melanomas can also express high p16 levels while being proliferative; indicating that bypass of p16-mediated senescence is a critical event in melanoma initiation. The identification of novel early stage melanoma genes that can bypass p16-mediated senescence is of potential biological significance not only because the details of how p16 suppresses melanoma is not clearly understood but this mechanism may also be dysregulated in other tumours with features of pre-malignancy.

In order to better characterise the mechanism of p16-mediated senescence and identify potential genes that can bypass its initiation, we have screened a human ORF lentiviral expression library, representing approximately 17000 unique full-length ORFs. High-content imaging of a melanoma cell line with inducible p16 was used to identify genes, which bypassed p16-induced senescence. This is the first time a genome scale gain-of-function screen has been performed in a human cell line using lentiviruses. We aim to validate hits in BRaf-induced and replicative senescence in primary melanocytes and examine the expression of these candidates in patient samples of naevi and primary melanomas. The identification of over-expressed genes and pathways that can bypass senescence induced by p16 will provide an improved understanding of the unique mechanism of p16-mediated senescence and may lead to the discovery of novel drug targets that selectively target a sub-type of primary melanoma.

Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Conference Paper
Collection: UQ Diamantina Institute Publications
 
Versions
Version Filter Type
Citation counts: Google Scholar Search Google Scholar
Created: Fri, 07 Jun 2013, 12:29:23 EST by Won Jae Lee on behalf of UQ Diamantina Institute