Am. J. Respir. Cell Mol. Biol.,
Volume 22, Number 6, June, 2000 747-754
Polycyclic Aromatic Hydrocarbon Carcinogens Increase Ubiquitination of
p21 Protein after the Stabilization of p53 and the Expression of p21
Yoichi
Nakanishi,
Xin-Hai
Pei,
Koichi
Takayama,
Feng
Bai,
Miiru
Izumi,
Kanehito
Kimotsuki,
Koji
Inoue,
Takahiro
Minami,
Hiroshi
Wataya,
and
Nobuyuki
Hara
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Polycyclic aromatic hydrocarbon carcinogens (PAHs) and their
metabolites have been found to result in a rapid accumulation of p53 gene product in human and mouse cells. However, the
induced p53 protein was reported to be transcriptionally inactive. In the present study, the induction of p53 target gene expression after the treatment with either benzo(a)pyrene
(B[a]P) or 1-nitropyrene (1-NP) was investigated. A marked induction of messenger RNA (mRNA) expressions of Mdm2, Bax,
and p21 was detected in wild-type p53-expressing cells after
the treatment with either B[a]P or 1-NP, whereas no significant change in mRNA expression of these genes was observed in p53-negative and mutant cells. 1-NP activated the p21 promoter in a p53-dependent manner. Binding activity of p53 to a
p53 consensus sequence increased after the treatment in wild-type p53-expressing cells. Nevertheless, the induced mRNA
levels of the p21 did not result in a proportional p21 protein
increase, indicating the possibility of post-transcriptional regulation of the protein. With the addition of MG-132, a proteasome inhibitor, to B[a]P or 1-NP treatments, both p21 and p53
protein levels were increased; however, the increase in p21
protein levels was significantly larger than the increase in p53
protein levels. PAHs treatment increased the level of ubiquitinated p21. These results suggest that the p21 product is degraded by the ubiquitin-proteasome system. We conclude
that PAHs-induced p53 protein is transcriptionally active.
