The functional importance of the interaction between p53 and HEXIM1.

Abstract

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.