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Title: The role of the polyadenylation site of the melanocortin 1 receptor in genertating MClR-TUBB3 chimeras and attenuation of TORCl delays the onset of replicative and RAS-induced cellular senescence
Author: Kolesnichenko , Marina
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2012
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PART I : Alternative 3' end processing of pre-mRNA greatly increases the complexity of the human genome by allowing the expression of different products from a single gene. Recent bioinformatic studies predict that a significant percentage of human genes are capable of intergenic splicing (intersplicing), thereby producing novel products by combining exons from two or more genes. To date, however, only a few reports provide evidence of splicing between adjacent genes ex vivo. Here we show that the human MC1R (Melanocortin 1 Receptor) gene contains an inefficient PAS that permits intersplicing from MC1R into its downstream neighbor, TUBB3 (Tubulin-Beta-III), generating at least two chimeric proteins with different localizations. We detected endogenous chimeric transcripts in human, but not in mouse melanocytes. Furthermore, expression of these transcripts could be induced through treatment of the human melanocytes with the MC1R agonist, alpha-MSH. We propose that regulation of suboptimal PAS may be a common feature that permits intersplicing between adjacent genes. PART II: Numerous stimuli, including oncogenic signaling, DNA damage, or eroded telomeres trigger proliferative arrest, termed cellular senescence. Accumulating evidence suggests that cellular senescence is a potent barrier to tumorigenesis in vivo, however oncogene induced senescence can also promote cellular transformation. Several oncogenes, whose overexpression results in cellular senescence, converge on the TOR (target of rapamycin) pathway. We therefore examined whether attenuation of TOR results in delay or reversal of cellular senescence. We demonstrated that senescence can be delayed, and some aspects of senescence can be reversed by inhibition of TOR, using either the TOR inhibitor rapamycin or by depletion of TORC1 (TOR Complex 1). Depletion of TORC2 fails to affect the course of replicative or RAS-induced senescence. Overexpression ofREDD1 (Regulated in DNA Damage Response and Development), a negative regulator ofTORC1, delays the onset of replicative senescence. These results indicate that TORC1 is an integral component of the signaling pathway that mediates cellular senescence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available