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Regulation of MDM2 stability and function by signalling from mTOR/S6K pathway

Wang, M-L; (2008) Regulation of MDM2 stability and function by signalling from mTOR/S6K pathway. Doctoral thesis , UCL (University College London). Green open access

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Ribosomal S6 kinase belongs to the AGC family of S/T kinases, which also include PKA, PKB/Akt, PKC, and SGK. The family of S6K consists of two isoforms, S6K1 and S6K2, which have cytoplasmic and nuclear splicing variants. Genetic and biochemical studies indicate that S6K is a key player in the regulation of cell growth, size, and the glucose metabolism. It has been also implicated in Gl to S transition of the cell cycle. The MDM2 is another important regulator of controlling the cell cycle. It was initially identified as a negative regulator of p53, and several other targets of MDM2, such as p2iwafl/cipl{rcub} were consequently discovered. The MDM2 protein is generally believed to be involved in p53-dependent and -independent pathways, and the importance of its role on cell cycle regulation and tumor development have been highlighted. Recent studies indicated that PI3K/Akt signalling promotes the phosphorylation of MDM2 at Serl66 and Serl86, which triggers the downregulation of p53. Here I present evidence that MDM2 is physically and functionally associated with S6K. Using mass spectrometry and phosphospecific antibody, I found that MDM2 is phosphorylated by S6K at Serl66. Phosphorylation of MDM2 at Serl66 closely correlates with the activation pattern of S6K when cells are treated with various mitogenic stimuli. Moreover, Serl66 is phosphorylated in cellular response to amino acid sufficiency, which is known to be mediated via the S6K, but not PKB/Akt pathway. Consistent with this data, Serl66 phosphorylation is highly sensitive to rapamycin, and in addition, mitogen-induced stability of MDM2 is inhibited in a dose-dependent manner by rapamycin. Interestingly, instead of regulating p53 transcriptional activity, I found that the S6K/MDM2 pathway signals to p21wafl/cipl. Taken together, my study indicates that mTOR/S6K pathway signals to MDM2 and may thereby provide insight into how rapamycin potentially blocks the Gl/S transition stage/phase of the cell cycle.

Type: Thesis (Doctoral)
Title: Regulation of MDM2 stability and function by signalling from mTOR/S6K pathway
Identifier: PQ ETD:593519
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/1446188
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