PMID:22948151

Citation	Lew, QJ, Chia, YL, Chu, KL, Lam, YT, Gurumurthy, M, Xu, S, Lam, KP, Cheong, N and Chao, SH (2012) Identification of HEXIM1 as a positive regulator of p53. J. Biol. Chem. 287:36443-54
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.
Links	PubMed PMC3476310 Online version:10.1074/jbc.M112.374157
Keywords	Antineoplastic Agents/pharmacology; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/metabolism; Cell Cycle Checkpoints/drug effects; Cell Cycle Checkpoints/genetics; Cell Cycle Checkpoints/physiology; Cell Line, Tumor; HEK293 Cells; Humans; Positive Transcriptional Elongation Factor B/genetics; Positive Transcriptional Elongation Factor B/metabolism; Protein Structure, Tertiary; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-mdm2/genetics; Proto-Oncogene Proteins c-mdm2/metabolism; RNA Polymerase II/genetics; RNA Polymerase II/metabolism; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology; Signal Transduction/radiation effects; Transcription, Genetic/drug effects; Transcription, Genetic/genetics; Transcription, Genetic/physiology; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; Ubiquitination/drug effects; Ubiquitination/physiology; Ubiquitination/radiation effects; Ultraviolet Rays; Up-Regulation/drug effects; Up-Regulation/physiology; Up-Regulation/radiation effects
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HEXI1		GO:1901798: positive regulation of signal transduction by p53 class mediator	ECO:0000315:		P		Fig 6.	complete CACAO 6812
HUMAN:HEXI1	involved_in	GO:1901798: positive regulation of signal transduction by p53 class mediator	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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