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Title: The post translational modification of the retinoblastoma protein
Author: Inche, Adam
ISNI:       0000 0001 3611 7743
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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The retinoblastoma protein (pRb) is a central figure in the control of not only the cell cycle, but also other cellular functions such as differentiation. The regulation of pRb function is through a variety of post translational modifications, either on pRb itself, or by the controlling influence of pRb on the post translational modification of the histone proteins. Phosphorylation of pRb is a key mechanism in the regulation of the cell cycle. pRb is also involved in the recruitment of histone methyltransferase (HMT) and acetyltransferase (HAT) to the chromatin to modify histones. Previous work within the group showed that pRb was subjected to acetylation by the HAT p300. The acetylation of pRb was shown to negatively influence phosphorylation by interfering with a proposed kinase binding site. Another group showed that acetylation of pRb may also be involved in the differentiation of myoblast cells. The work presented here characterises, for the first time, the methylation of pRb by the HMT Set7/9, previously shown to methylate p53. This post translational modification was identified by a combination of ill vitro mutational analysis and mass spectroscopy. The site of methylation was shown to be at lysine 873 (K873), the same region that was subjected to acetylation by the HAT p300. It was also shown that methylation at K873 occurs il1 vivo and is up regulated in response to myoblast differentiation. The ability for these cells to differentiate is compromised when a mutant of pRb is used that cannot be methylated at position 873. . The methylation ofpRb also seems to exert a regulatory control over other post translational modifications that occur on pRb. It was shown that pRb methylated by Set7/9 was able to reduce -acetylation at positions 873/4. The over expression of Set7/9 in cells was also shown to specifically negatively affect the phosphorylation of S811. This site has been implicated in the regulation cell cycle exit, and therefore supports the theory that methylation of pRb is required for the progression of differentiation. It is unclear at this time if the regulation of phosphorylation at S811 is as a consequence of methylation at K873, or at a secondary site that was identified by in vitro mass spectroscopy at K810.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available