The functional importance of the interaction between p53 and HEXIM1.

• Main Author: Chia, Yi Ling.
• Other Authors: School of Biological Sciences
• Format: Final Year Project
• Language: English
• Published: 2011
• Subjects: DRNTU::Science::Biological sciences::Molecular biology
• Online Access: http://hdl.handle.net/10356/44231
• Institution: Nanyang Technological University

Tumor suppressor p53 is an important cell cycle checkpoint protein, regulating cell cycle arrest and apoptotic response. Suppression of p53 functions account for 50% of human tumors. Thus, re-activation of p53 provides an attractive therapeutic target in cancer therapy. Positive transcription elongation factor b (P-TEFb) is an important kinase complex which phosphorylates both the carboxyl-terminal domain (CTD) of RNA polymerase II (RNAPII) and the negative transcription elongation factors (NTEF), to initiate progressive elongation. Inhibition of P-TEFb complex would result in the global inhibition of mRNA synthesis. Therefore, Hexamethylene bis-acetamide inducible protein 1(HEXIM1) serves as an important negative regulator of P-TEFb complex to ensure regulated transcription initiation. Previous studies have reported a possible connection between HEXIM1 and cancer formation. HEXIM1 was shown to interact with two key regulators of p53, namely the human double minute 2 (HDM2) and nucleoplasmin. In this study, a novel interaction between HEXIM1 and p53 is demonstrated. Over-expression of HEXIM1 results in p53 stabilization. In contrast, knockdown of HEXIM1 by specific short hairpin RNA (shRNA) results in the decrease of p53 level. Moreover, the over-expression of HEXIM1 is able to induce the expression level of p53 downstream targets, such as p21 and p53 up-regulated modulator of apoptosis (PUMA), and to increase the phosphorylation on p53 serine 33 and 392 residues. More importantly, we are able to observe a significant increase in HEXIM1-p53 interaction, accompanied with elevated p53 level, across UV and different p53-inducing drug/compound treatments. Collectively, our results strongly suggest that HEXIM1-p53 interaction is important for p53 stabilization, revealing a novel insight into the role of HEXIM1 as a positive regulator of p53.