Cooperation of a Single Lysine Mutation and a C-terminal Domain in the Cytoplasmic Sequestration of the p53 Protein

Liang, Shun-Hsin; Hong, David; Clarke, Michael F.

doi:10.1074/jbc.273.31.19817

Cited by 47 publications

(50 citation statements)

References 39 publications

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“…However, because mutations were not confirmed with DNA sequencing, these data should be interpreted with caution. Liang et al 14 used colon and breast cancer cell lines and found that a p53 mutation in codon 305 was related to the p53 protein being sequestered to the cytoplasm. They further demonstrated that, together with a cytoplasmic sequestration domain at the C-terminus (amino acid 326 to 355) of the p53 protein, lysine 305 was necessary for nuclear import of the protein.…”

Section: Discussionmentioning

confidence: 99%

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

2001

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Previous studies have shown that nuclear p53 over-expression is an indicator of p53 mutations whereas cytoplasmic p53 accumulation is related to wild-type p53 in several kinds of tumors. Cytoplasmic p53 accumulation has been demonstrated to be an independent prognostic factor in colorectal adenocarcinomas. The purpose was to examine whether mutations occur in cases with p53 accumulated in the cytoplasm and whether there are any differences in the frequency and characteristics of p53 mutations in different staining patterns. In the present study, we identified p53 mutations using PCR single-strand conformation polymorphism (SSCP) and DNA sequencing in 75 primary colorectal adenocarcinomas with different staining patterns (negative, nucleus, cytoplasm, nucleus and cytoplasm). The results show that the frequency and nature of mutations in tumors with cytoplasmic p53 accumulation were similar to those with nuclear p53 expression. However, the tumors with accumulation in both the nucleus and cytoplasm demonstrated a higher mutation rate. We suppose that the role of cytoplasmic p53 accumulation in predicting prognosis in patients with colorectal cancer may be dependent on both mutational and non-mutational mechanisms. Wild-type p53 protein functions as a transregulator of genes involved in DNA synthesis, DNA repair and apoptosis. 1 Wild-type p53 is normally low. However, p53 that is inactivated through mutations, deletions or binding to other proteins results in p53 protein accumulation which can be detected by immunohistochemistry. 2 Over-expression of the p53 protein has been reported in approximately 50% of colorectal cancers. 3 The majority of investigators have focused on nuclear p53 expression and considered it as an indication of p53 gene mutation. Actually, p53 cytoplasmic accumulation is present in different types of tumors including colorectal cancer, 4 -7 breast cancer 5,8 and neuroblastoma. 8 However, the studies on these tumors showed that cytoplasmic p53 was associated with wild-type p53. 9,10 To our knowledge, investigators have not used DNA sequencing to investigate p53 mutations in human colorectal cancer tissue with cytoplasmic p53 over-expression. Several groups have shown that cytoplasmic p53 accumulation is associated with advanced tumor stage and is an independent prognostic factor in patients with colorectal cancer, whereas nuclear accumulation is not. 6,8,11 Further, the patients with p53-positive tumors in both the nucleus and cytoplasm had the most unfavorable outcome. 6 We previously found that cytoplasmic p53, but not nuclear p53, is associated with heat shock proteins in colorectal cancer. 12 These results indicate that the characteristics and roles of the subcellular localization of p53 protein may be different in controlling p53 function.In our study, we used PCR single-strand conformation polymorphism (SSCP) and DNA sequencing to evaluate p53 mutations with different patterns of p53 protein accumulation (negative, nucleus, cytoplasm, nucleus and cytoplasm) in 75 colorectal cancers from ...

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Section: Discussionmentioning

confidence: 99%

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

2001

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“…As p53 is too large to passively di use across the nuclear pore, its subcellular distribution must be mediated by the cell's protein import and export machinery. Facilitated nuclear import of p53 occurs via three lysine-rich nuclear localization signals (NLSs) in the Cterminus at amino acids 305±322 (NLS I), 369-375 (NLS II), and 379±384 (NLS III) (Liang et al, 1998;Shaulsky et al, 1990b). NLS I appears to be the primary NLS as mutation of this sequence alone abrogates p53 nuclear import.…”

Section: Linking P53 Activation With Its Subcellular Localizationmentioning

confidence: 99%

“…The cdc2/cdk2 phosphorylation site at S315 and the PCAF acetylation site at K320 both lie within NLS I, and it is not di cult to imagine that these modi®cations could a ect association with a nuclear import receptor, especially since the phosphorylation of NLSs has been reported to regulate the import of other proteins such as SWI5 (Jans et al, 1995;Moll et al, 1991), Lamin B2 (Hennekes et al, 1993), v-Jun (Tagawa et al, 1995, and CaM kinase II (Heist et al, 1998). However, since an S315A mutation seems to have no e ect on p53 nuclear localization (Liang et al, 1998), it remains to be determined what role these modi®cations may play.…”

Section: Linking P53 Activation With Its Subcellular Localizationmentioning

confidence: 99%

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

et al. 1999

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p53 activation by diverse stresses involves post-translational modi®cations that alter its structure and result in its nuclear accumulation. We will discuss several unresolved topics regarding p53 regulation which are currently under investigation. DNA damage is perhaps the best-studied stress which activates p53, and recent data implicate phosphorylation at N-terminal serine residues as critical in this process. We discuss recent data regarding the potential kinases which modify p53 and the possible role of the resulting phosphorylation events. By contrast, much less is understood about agents which disrupt the mitotic spindle. The cell cycle phase, induction signal, and biochemical mechanism of the reversible arrest induced by microtubule disruption are currently under investigation. Finally, a key event in response to any genotoxic stress is the accumulation of p53 in the nucleus. The factors which determine the steady state level of p53 are starting to be elucidated, but the mechanisms responsible for nuclear accumulation and nuclear export remain controversial. We discuss new studies revealing a mechanism for nuclear retention of p53, and the potential contributions of MDM2 to this process.

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“…In the C-terminal domain, nuclear-localization signals mediate translocation of p53 to the nucleus (Shaulsky et al, 1990;Liang et al, 1998). Post-translational modifications of this region modulate the specific activity of p53 in vivo and, in unstressed cells, the C-terminal domain maintains p53 in a non-DNA-binding form (Levine, 1997;Hupp et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Øster

Bundgaard

Hupp

et al. 2008

Journal of General Virology

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Here, we demonstrate that human herpesvirus 6B (HHV-6B) infection upregulates the tumour suppressor p53 and induces phosphorylation of p53 at Ser392. Interestingly, phosphorylation at the equivalent site has previously been shown to correlate with p53 tumour suppression in murine models. Although the signalling pathways leading to Ser392 phosphorylation are poorly understood, they seem to include casein kinase 2 (CK2), double-stranded RNA-activated protein kinase (PKR), p38 or cyclin-dependent kinase 9 (Cdk9). By using column chromatography and in vitro kinase assays, CK2 and p38, but not PKR or Cdk9, eluted in column fractions that phosphorylated p53 at Ser392. However, treatment of cells with neither the CK2 and Cdk9 inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) nor p38 kinase inhibitors reduced HHV-6B-induced Ser392 phosphorylation significantly. Knockdown of the CK2β subunit or p38α by small interfering RNA had no effect on HHV-6B-induced phosphorylation of p53 at Ser392. Thus, HHV-6B induces p53 Ser392 phosphorylation by an atypical pathway independent of CK2 and p38 kinases, whereas mitogen-activated protein (MAP) kinase signalling pathways are involved in viral replication.

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Cooperation of a Single Lysine Mutation and a C-terminal Domain in the Cytoplasmic Sequestration of the p53 Protein

Cited by 47 publications

References 39 publications

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

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