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Role of p53 in Cell Death and Human Cancers.

Ozaki T, Nakagawara A - Cancers (Basel) (2011)

Bottom Line: Indeed, mutant p53 has an oncogenic potential.Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis.Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Anti-tumor Research, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan. akiranak@chiba-cc.jp.

ABSTRACT
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers.

No MeSH data available.


Related in: MedlinePlus

Structure of p53 variants. TA, transactivation domain; DB, sequence-specific DNA-binding domain; OD, oligomerization domain. Estimated molecular weights are also shown.
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f3-cancers-03-00994: Structure of p53 variants. TA, transactivation domain; DB, sequence-specific DNA-binding domain; OD, oligomerization domain. Estimated molecular weights are also shown.

Mentions: In addition to the alternative translation product of p53, Bourdon et al. described that human p53 encodes multiple variants arising from alternative splicing and alternative promoter usage [127, 128]. According to their results, they found an internal promoter within intron 4 of human p53 by using GeneRacer PCR-based strategy. Finally, they discovered the NH2-terminally truncated variant initiated at codon 133 (Δ133p53) distinct from p53/47. Δ133p53 lacks NH2-terminal transactivation domain and Pro-rich domain. They extended their study to identify the other variant forms of p53 by RT-PCR. They found that the alternative splicing event of intron 9 leads to the generation of p53β and p53γ, which delete the COOH-terminal oligomerization domain. Collectively, human p53 encodes p53, p53β, p53γ, Δ133p53, Δ133p53β, Δ133p53γ, Δ40p53, Δ40p53β, and Δ40p53γ. Δ40p53 corresponds to p53/47 (Figure 3). Based on their results, p53β was localized largely in cell nucleus, whereas p53γ was detectable both in cell nucleus and cytoplasm. Additionally, Δ133p53β was expressed both in cell nucleus and cytoplasm; however, Δ133p53γ was detected only in cytoplasm. Extensive expression studies demonstrated that p53 variants are expressed in a wide variety of human normal tissues but in a tissue-dependent manner. In addition, DNA damage-mediated accumulation of p53β and Δ133p53β were not detectable. Intriguingly, Δ133p53 was detected in 24 out of 30 primary breast cancers. Since Δ133p53 acts as a dominant-negative inhibitor toward wild-type p53, it is possible that Δ133p53 is involved in the development of breast cancers bearing wild-type p53.


Role of p53 in Cell Death and Human Cancers.

Ozaki T, Nakagawara A - Cancers (Basel) (2011)

Structure of p53 variants. TA, transactivation domain; DB, sequence-specific DNA-binding domain; OD, oligomerization domain. Estimated molecular weights are also shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756401&req=5

f3-cancers-03-00994: Structure of p53 variants. TA, transactivation domain; DB, sequence-specific DNA-binding domain; OD, oligomerization domain. Estimated molecular weights are also shown.
Mentions: In addition to the alternative translation product of p53, Bourdon et al. described that human p53 encodes multiple variants arising from alternative splicing and alternative promoter usage [127, 128]. According to their results, they found an internal promoter within intron 4 of human p53 by using GeneRacer PCR-based strategy. Finally, they discovered the NH2-terminally truncated variant initiated at codon 133 (Δ133p53) distinct from p53/47. Δ133p53 lacks NH2-terminal transactivation domain and Pro-rich domain. They extended their study to identify the other variant forms of p53 by RT-PCR. They found that the alternative splicing event of intron 9 leads to the generation of p53β and p53γ, which delete the COOH-terminal oligomerization domain. Collectively, human p53 encodes p53, p53β, p53γ, Δ133p53, Δ133p53β, Δ133p53γ, Δ40p53, Δ40p53β, and Δ40p53γ. Δ40p53 corresponds to p53/47 (Figure 3). Based on their results, p53β was localized largely in cell nucleus, whereas p53γ was detectable both in cell nucleus and cytoplasm. Additionally, Δ133p53β was expressed both in cell nucleus and cytoplasm; however, Δ133p53γ was detected only in cytoplasm. Extensive expression studies demonstrated that p53 variants are expressed in a wide variety of human normal tissues but in a tissue-dependent manner. In addition, DNA damage-mediated accumulation of p53β and Δ133p53β were not detectable. Intriguingly, Δ133p53 was detected in 24 out of 30 primary breast cancers. Since Δ133p53 acts as a dominant-negative inhibitor toward wild-type p53, it is possible that Δ133p53 is involved in the development of breast cancers bearing wild-type p53.

Bottom Line: Indeed, mutant p53 has an oncogenic potential.Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis.Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Anti-tumor Research, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan. akiranak@chiba-cc.jp.

ABSTRACT
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers.

No MeSH data available.


Related in: MedlinePlus