PMID- 22948151
OWN - NLM
STAT- MEDLINE
DCOM- 20121228
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 43
DP  - 2012 Oct 19
TI  - Identification of HEXIM1 as a positive regulator of p53.
PG  - 36443-54
LID - 10.1074/jbc.M112.374157 [doi]
AB  - 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.
FAU - Lew, Qiao Jing
AU  - Lew QJ
AD  - Expression Engineering Group, Bioprocessing Technology Institute, Agency for 
      Science, Technology, and Research (A*STAR), Singapore 138668, Singapore.
FAU - Chia, Yi Ling
AU  - Chia YL
FAU - Chu, Kai Ling
AU  - Chu KL
FAU - Lam, Yuen Ting
AU  - Lam YT
FAU - Gurumurthy, Meera
AU  - Gurumurthy M
FAU - Xu, Shengli
AU  - Xu S
FAU - Lam, Kong Peng
AU  - Lam KP
FAU - Cheong, Nge
AU  - Cheong N
FAU - Chao, Sheng-Hao
AU  - Chao SH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120904
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BBC3 protein, human)
RN  - 0 (HEXIM1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (TP53 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
RN  - EC 2.7.11.- (Positive Transcriptional Elongation Factor B)
RN  - EC 2.7.7.- (RNA Polymerase II)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis Regulatory Proteins/genetics/metabolism
MH  - Cell Cycle Checkpoints/drug effects/genetics/physiology
MH  - Cell Line, Tumor
MH  - HEK293 Cells
MH  - Humans
MH  - Positive Transcriptional Elongation Factor B/genetics/metabolism
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Proto-Oncogene Proteins c-mdm2/genetics/metabolism
MH  - RNA Polymerase II/genetics/metabolism
MH  - RNA-Binding Proteins/genetics/*metabolism
MH  - Signal Transduction/drug effects/*physiology/radiation effects
MH  - Transcription Factors
MH  - Transcription, Genetic/drug effects/genetics/*physiology
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
MH  - Ubiquitination/drug effects/*physiology/radiation effects
MH  - Ultraviolet Rays
MH  - Up-Regulation/drug effects/*physiology/radiation effects
PMC - PMC3476310
EDAT- 2012/09/06 06:00
MHDA- 2012/12/29 06:00
PMCR- 2013/10/19
CRDT- 2012/09/06 06:00
PHST- 2012/09/06 06:00 [entrez]
PHST- 2012/09/06 06:00 [pubmed]
PHST- 2012/12/29 06:00 [medline]
PHST- 2013/10/19 00:00 [pmc-release]
AID - S0021-9258(20)62618-7 [pii]
AID - M112.374157 [pii]
AID - 10.1074/jbc.M112.374157 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Oct 19;287(43):36443-54. doi: 10.1074/jbc.M112.374157. Epub 
      2012 Sep 4.