title: Identification of HEXIM1 as a positive regulator of p53.
abstract: Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which regulates the transcription elongation of RNA polymerase II and controls 60-70% of mRNA synthesis. Our previous studies show that HEXIM1 interacts with two key p53 regulators, nucleophosmin and human double minute-2 protein (HDM2), implying a possible connection between HEXIM1 and the p53 signaling pathway. Here we report the interaction between p53 and HEXIM1 in breast cancer, acute myeloid leukemia, and colorectal carcinoma cells. The C-terminal regions of p53 and HEXIM1 are required for the protein-protein interaction. Overexpression of HEXIM1 prevents the ubiquitination of p53 by HDM2 and enhances the protein stability of p53, resulting in up-regulation of p53 target genes, such as Puma and p21. Induction of p53 can be achieved by several means, such as UV radiation and treatment with anti-cancer agents (including doxorubicin, etoposide, roscovitine, flavopiridol, and nutlin-3). Under all the conditions examined, elevated protein levels of p53 are found to associate with the increased p53-HEXIM1 interaction. In addition, knockdown of HEXIM1 significantly inhibits the induction of p53 and releases the cell cycle arrest caused by p53. Finally, the transcription of the p53 target genes is regulated by HEXIM1 in a p53-dependent fashion. Our results not only identify HEXIM1 as a positive regulator of p53, but also propose a novel molecular mechanism of p53 activation caused by the anti-cancer drugs and compounds.
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology, and Research (A*STAR), Singapore 138668, Singapore.
authors.forename: Qiao Jing
authors.initials: QJ
authors.lastname: Lew
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Chia
authors.forename: Kai Ling
authors.initials: KL
authors.lastname: Chu
authors.forename: Yuen Ting
authors.initials: YT
authors.lastname: Lam
authors.forename: Meera
authors.initials: M
authors.lastname: Gurumurthy
authors.forename: Shengli
authors.initials: S
authors.lastname: Xu
authors.forename: Kong Peng
authors.initials: KP
authors.lastname: Lam
authors.forename: Nge
authors.initials: N
authors.lastname: Cheong
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Chao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C476123:HEXIM1 protein, human; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II