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Title: Functional analysis of the KDM5B demethylase : in vitro and in vivo studies
Author: Catchpole, Steven
ISNI:       0000 0004 5350 0295
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2014
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The KDM5 family consists of four proteins, namely KDM5A, KDM5B, KDM5C and KDM5D. The KDM5 family of demethylase proteins counteract the tri-methylation of H3K4 and can function as transcriptional repressors. They can form a number of different multi-protein complexes that contain other chromatin-modifying factors and co-factors that aid in the recruitment of the protein complex to the genome, whilst also possessing the ability to bind to DNA directly through the ARID domain. Furthermore the KDM5 family has also been implicated in mediating nuclear receptor signalling. The KDM5 family are highly homologous and where co-expressed may act redundantly. A picture is emerging where the KDM5 family may dictate the shift in balance between cellular proliferation and differentiation and are therefore important during development. Although the KDM5 demethylase activity has attracted the greatest attention, it is apparent that this family is an important multi-faceted group of proteins. To study the function of KDM5B two knockout murine lines were generated. The Kdm5b null murine line resulted in early embryonic lethality, whereas a second murine line expressing a KDM5B protein lacking the ARID domain (!ARID) was viable and fertile but displayed a mammary gland phenotype, where terminal end bud development and side branching were delayed at puberty. Since intact oestrogen receptor (ER alpha) signaling is a prerequisite for nulliparous mammary gland development we examined the expression of the progesterone receptor in the adult nulliparous KDM5B !ARID murine mammary gland and found levels to be reduced as compared to the wild-type. Furthermore, co-immunoprecipition of tagged human KDM5B and ER alpha proteins demonstrated an in vivo interaction. These studies suggest that KDM5B is required during embryonic development and may be involved in the ER alpha signaling pathway during nulliparous mammary gland development. Our analysis of the C57BL/6J-Kdm5b !ARID pregnant mammary gland showed a delay in mammary gland morphogenesis and the female could nurse her pups at parturition. Investigation into the molecular mechanisms that may relate to this showed that KDM5B expression is required to positively regulate the PRLR/JAK2/STAT5 signalling pathway associated with mammary gland development during gestation.
Supervisor: Taylor-Papadimitriou, Joyce; Burchell, Joy Marilyn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available