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postgraduate thesis: Role(s) of p53/p63 in chondrocyte re-differentiation upon activation of ER stress

TitleRole(s) of p53/p63 in chondrocyte re-differentiation upon activation of ER stress
Authors
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Pei, L. S. [貝念祖]. (2012). Role(s) of p53/p63 in chondrocyte re-differentiation upon activation of ER stress. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4807968
AbstractEndoplasmic Reticulum (ER) stress signal is a cellular response to various insults including abnormal protein folding load, activating the unfolded protein response. Under severe ER stress, apoptosis will occur in most cell types. Interestingly, this does not happen in a disease model for Metaphyseal chondrodysplasia type Schmid (MCDS), where ER stress was activated in the hypertrophic zone of the growth plate where mutant collagen X proteins that cannot be folded correctly is expressed. Instead of normal progression from proliferating chondrocytes (PCs) to hypertrophic chondrocytes (HCs) and conversion to bone, HCs in MCDS mice undergo re-differentiation to PCs as a survival strategy due to an activation of ER stress. Transcription factors are known to be important in regulating differentiation. p53 family members, as transcription factors, are known to play important roles in developmental processes including cellular reprogramming, thus, we hypothesize that the ectopic expression of key transcription factors, p53 and TAp63, which are activated by ER stress is involved in HC re-differentiation. p53 is normally expressed in late PCs, Pre-HCs, and upper HCs, while TAp63 is expressed in PCs and Pre-HCs suggesting they may have roles in chondrocyte differentiation. p53 activated under ER stress in HCs are nuclear localized in MCDS mice, but did not invoke the apoptotic programme. In this project, using quantitative analyse to study the expression level of p53 and p63 isoforms, it was confirmed that p53 and TAp63γ are in part transcriptionally activated upon ER stress. From functional study by inactivating p53 in MCDS mice, it was shown that p53 alone was not sufficient to mediate re-differentiation. Given that TAp63γ isoforms is also highly upregulated upon ER stress, and the negative regulator, ΔNp63, is downregulated, this combination of change in gene expression also need to be considered. Furthermore, known regulators of p53 and p63 activity such as ASPP1 and iASPP are also differentially expressed in HCs, and are altered upon activation of ER stress favouring cell survival. Thus, it would be important to evaluate the combination of TAp63 in the re-differentiation process from conditional inactivation of p63 or in combination with p53 to gain a clearer understanding of the contribution and relationship of these transcription factors in the survival strategy of stressed HCs.
DegreeMaster of Philosophy
SubjectCartilage cells
Endoplasmic reticulum
p53 protein
p53 antioncogene
Dept/ProgramBiochemistry
Persistent Identifierhttp://hdl.handle.net/10722/198926

 

DC FieldValueLanguage
dc.contributor.authorPei, Lim-cho, Steven-
dc.contributor.author貝念祖-
dc.date.accessioned2014-07-18T23:11:57Z-
dc.date.available2014-07-18T23:11:57Z-
dc.date.issued2012-
dc.identifier.citationPei, L. S. [貝念祖]. (2012). Role(s) of p53/p63 in chondrocyte re-differentiation upon activation of ER stress. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4807968-
dc.identifier.urihttp://hdl.handle.net/10722/198926-
dc.description.abstractEndoplasmic Reticulum (ER) stress signal is a cellular response to various insults including abnormal protein folding load, activating the unfolded protein response. Under severe ER stress, apoptosis will occur in most cell types. Interestingly, this does not happen in a disease model for Metaphyseal chondrodysplasia type Schmid (MCDS), where ER stress was activated in the hypertrophic zone of the growth plate where mutant collagen X proteins that cannot be folded correctly is expressed. Instead of normal progression from proliferating chondrocytes (PCs) to hypertrophic chondrocytes (HCs) and conversion to bone, HCs in MCDS mice undergo re-differentiation to PCs as a survival strategy due to an activation of ER stress. Transcription factors are known to be important in regulating differentiation. p53 family members, as transcription factors, are known to play important roles in developmental processes including cellular reprogramming, thus, we hypothesize that the ectopic expression of key transcription factors, p53 and TAp63, which are activated by ER stress is involved in HC re-differentiation. p53 is normally expressed in late PCs, Pre-HCs, and upper HCs, while TAp63 is expressed in PCs and Pre-HCs suggesting they may have roles in chondrocyte differentiation. p53 activated under ER stress in HCs are nuclear localized in MCDS mice, but did not invoke the apoptotic programme. In this project, using quantitative analyse to study the expression level of p53 and p63 isoforms, it was confirmed that p53 and TAp63γ are in part transcriptionally activated upon ER stress. From functional study by inactivating p53 in MCDS mice, it was shown that p53 alone was not sufficient to mediate re-differentiation. Given that TAp63γ isoforms is also highly upregulated upon ER stress, and the negative regulator, ΔNp63, is downregulated, this combination of change in gene expression also need to be considered. Furthermore, known regulators of p53 and p63 activity such as ASPP1 and iASPP are also differentially expressed in HCs, and are altered upon activation of ER stress favouring cell survival. Thus, it would be important to evaluate the combination of TAp63 in the re-differentiation process from conditional inactivation of p63 or in combination with p53 to gain a clearer understanding of the contribution and relationship of these transcription factors in the survival strategy of stressed HCs.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshCartilage cells-
dc.subject.lcshEndoplasmic reticulum-
dc.subject.lcshp53 protein-
dc.subject.lcshp53 antioncogene-
dc.titleRole(s) of p53/p63 in chondrocyte re-differentiation upon activation of ER stress-
dc.typePG_Thesis-
dc.identifier.hkulb4807968-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplineBiochemistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4807968-
dc.date.hkucongregation2012-

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