Endoplasmic 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. / published_or_final_version / Biochemistry / Master / Master of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/198926 |
| Date | January 2012 |
| Creators | Pei, Lim-cho, Steven, 貝念祖 |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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