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Title: The expression of an EMT regulator ZEB2 is controlled by a new destabilisation motif
Author: Wan Makhtar, Wan Ratmaazila
ISNI:       0000 0004 5355 5632
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2015
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Epithelial-mesenchymal transitions (EMT) are genetic re-differentiation programs which generate motile and invasive cells during normal embryonic development and cancer metastasis. ZEB1 and ZEB2 are two-handed zinc finger transcription repressors which belong to the Zinc finger E-box (ZEB) protein family. These proteins inhibit transcription of E-cadherin gene and induce EMT in vitro. However, the regulation of ZEB genes is still incompletely understood. Given an important role for both proteins in EMT in normal development and cancer metastasis, better understanding of molecular mechanisms controlling their expression is an important challenge. Intriguingly, a comparative expression analysis of ZEB1 and ZEB2 proteins in several cancer cell lines indicated that ZEB1 protein was expressed at much higher level than ZEB2 mostly in mesenchymal carcinoma cells. On the other hand, these cell lines contained high levels of ZEB2 and ZEB1 mRNA. Therefore, we suggested that an additional specific control mechanism limiting ZEB2 protein synthesis exists; and we addressed this issue in greater detail. We showed that a protein motif adjacent to the smad-binding domain within ZEB2 protein induced ribosome stalling and compromised ZEB2 translation. The activity of this motif was dependent on triplets of rare codons, Leu(UUA)-Gly(GGU)-Val(GUA). However, introducing these rare codons in the ZEB1 region had no effect on ZEB1 protein expression. In conclusion, my study suggests that rare codon play regulatory role in the context of appropriate protein structures and may influence configuration of EMT programs in cancer cells.
Supervisor: Tulchinsky, Eugene Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available