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Role of p53 in Anticancer Drug Treatment- and Radiation-Induced Injury in Normal Small Intestine.

Jin S - Cancer Biol Med (2012)

Bottom Line: In the human gastrointestinal tract, the functional mucosa of the small intestine has the highest capacity for absorption of nutrients and rapid proliferation rates, making it vulnerable to chemoradiotherapy.A traditional p53 inhibitor and two other molecules that exhibit strong protective effects on normal small intestinal epithelium during anticancer drug treatment and radiation therapy are introduced in this work.The objective of this review was to update current knowledge regarding potential mechanisms and targets that inhibit the side effects induced by chemoradiotherapy.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD 21210, USA.

ABSTRACT
In the human gastrointestinal tract, the functional mucosa of the small intestine has the highest capacity for absorption of nutrients and rapid proliferation rates, making it vulnerable to chemoradiotherapy. Recent understanding of the protective role of p53-mediated cell cycle arrest in the small intestinal mucosa has led researchers to explore new avenues to mitigate mucosal injury during cancer treatment. A traditional p53 inhibitor and two other molecules that exhibit strong protective effects on normal small intestinal epithelium during anticancer drug treatment and radiation therapy are introduced in this work. The objective of this review was to update current knowledge regarding potential mechanisms and targets that inhibit the side effects induced by chemoradiotherapy.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of p53 signaling in response to anticancer drug treatment and radiation therapy in crypt cells of the small intestine and action sites of 3 molecules (PFT, DFMO, and LPA). In response to DNA damage, p53 accumulation leads to the activation of three pathways involved in (1) apoptosis, (2) cell cycle arrest, and (3) DNA repair. The transcriptional activity of p53 increases the expression levels of proteins responsible for the three pathways, such as p21 and Bax. The cytosol function of p53 also directly induces the MOMP. PFT-α inhibits the transcriptional activity of p53 [28], whereas PFT-µ binds p53 to attenuate the binding affinity of anti-apoptotic proteins, such as Bcl-XL[29]. DFMO increases the expression of p21 but inhibits that of Bax [30]. LPA blocks the translocation of Bax from cytosol to mitochondria [31], accelerates the protein degradation of pro-apoptotic Siva-1 [32,33], and increases the protein expression of Bcl-XL[34]. The effect of LPA on p21 in response to DNA damage is currently unknown. In some conditions, such as high-dose radiation for cancer treatment, blocking p53 (such as in p53 KO mice) in crypts of the small intestine leads to mitotic catastrophe, a type of cell death occurring during mitosis, as a result of DNA damage [35]. Inhibiting the p53-mediated p21 pathway is a major mechanism responsible for mitotic catastrophe in cells with unrepaired DNA. The p53-mediated cell cycle arrest pathway is hypothesized to offer cells a time window to process DNA repair in response to DNA damage. The numbers within parentheses indicate the sources of these findings. Detailed mechanisms related to apoptosis have been reviewed elsewhere [12-14].
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f2: Schematic representation of p53 signaling in response to anticancer drug treatment and radiation therapy in crypt cells of the small intestine and action sites of 3 molecules (PFT, DFMO, and LPA). In response to DNA damage, p53 accumulation leads to the activation of three pathways involved in (1) apoptosis, (2) cell cycle arrest, and (3) DNA repair. The transcriptional activity of p53 increases the expression levels of proteins responsible for the three pathways, such as p21 and Bax. The cytosol function of p53 also directly induces the MOMP. PFT-α inhibits the transcriptional activity of p53 [28], whereas PFT-µ binds p53 to attenuate the binding affinity of anti-apoptotic proteins, such as Bcl-XL[29]. DFMO increases the expression of p21 but inhibits that of Bax [30]. LPA blocks the translocation of Bax from cytosol to mitochondria [31], accelerates the protein degradation of pro-apoptotic Siva-1 [32,33], and increases the protein expression of Bcl-XL[34]. The effect of LPA on p21 in response to DNA damage is currently unknown. In some conditions, such as high-dose radiation for cancer treatment, blocking p53 (such as in p53 KO mice) in crypts of the small intestine leads to mitotic catastrophe, a type of cell death occurring during mitosis, as a result of DNA damage [35]. Inhibiting the p53-mediated p21 pathway is a major mechanism responsible for mitotic catastrophe in cells with unrepaired DNA. The p53-mediated cell cycle arrest pathway is hypothesized to offer cells a time window to process DNA repair in response to DNA damage. The numbers within parentheses indicate the sources of these findings. Detailed mechanisms related to apoptosis have been reviewed elsewhere [12-14].

Mentions: The p53 gene encodes protein containing 393 amino acid residues [25]. In non-stressed cells, p53 has a short half-life (~20 min), and its cellular concentration is thus maintained at a relatively low level [26]. When the cells are stressed by events from inside or (and) outside the cells, such as DNA damage induced by anticancer drug treatment or radiation therapy, p53 dissociates from its binding partner, MDM2, a critical negative regulator of p53, and is activated by post-translation modification [27]. As shown in Figure 2, p53 activation leads to G1-phase cell cycle arrest and DNA repair via transcriptional upregulation of related genes, such as p21 [36]. Successful DNA repair will allow cells to proceed with the cell cycle. Under DNA damage conditions, p53 also increases the expression of genes responsible for cell apoptosis, such as Bax [37] and p53 upregulated modulator of apoptosis (Puma) [38].


Role of p53 in Anticancer Drug Treatment- and Radiation-Induced Injury in Normal Small Intestine.

Jin S - Cancer Biol Med (2012)

Schematic representation of p53 signaling in response to anticancer drug treatment and radiation therapy in crypt cells of the small intestine and action sites of 3 molecules (PFT, DFMO, and LPA). In response to DNA damage, p53 accumulation leads to the activation of three pathways involved in (1) apoptosis, (2) cell cycle arrest, and (3) DNA repair. The transcriptional activity of p53 increases the expression levels of proteins responsible for the three pathways, such as p21 and Bax. The cytosol function of p53 also directly induces the MOMP. PFT-α inhibits the transcriptional activity of p53 [28], whereas PFT-µ binds p53 to attenuate the binding affinity of anti-apoptotic proteins, such as Bcl-XL[29]. DFMO increases the expression of p21 but inhibits that of Bax [30]. LPA blocks the translocation of Bax from cytosol to mitochondria [31], accelerates the protein degradation of pro-apoptotic Siva-1 [32,33], and increases the protein expression of Bcl-XL[34]. The effect of LPA on p21 in response to DNA damage is currently unknown. In some conditions, such as high-dose radiation for cancer treatment, blocking p53 (such as in p53 KO mice) in crypts of the small intestine leads to mitotic catastrophe, a type of cell death occurring during mitosis, as a result of DNA damage [35]. Inhibiting the p53-mediated p21 pathway is a major mechanism responsible for mitotic catastrophe in cells with unrepaired DNA. The p53-mediated cell cycle arrest pathway is hypothesized to offer cells a time window to process DNA repair in response to DNA damage. The numbers within parentheses indicate the sources of these findings. Detailed mechanisms related to apoptosis have been reviewed elsewhere [12-14].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643648&req=5

f2: Schematic representation of p53 signaling in response to anticancer drug treatment and radiation therapy in crypt cells of the small intestine and action sites of 3 molecules (PFT, DFMO, and LPA). In response to DNA damage, p53 accumulation leads to the activation of three pathways involved in (1) apoptosis, (2) cell cycle arrest, and (3) DNA repair. The transcriptional activity of p53 increases the expression levels of proteins responsible for the three pathways, such as p21 and Bax. The cytosol function of p53 also directly induces the MOMP. PFT-α inhibits the transcriptional activity of p53 [28], whereas PFT-µ binds p53 to attenuate the binding affinity of anti-apoptotic proteins, such as Bcl-XL[29]. DFMO increases the expression of p21 but inhibits that of Bax [30]. LPA blocks the translocation of Bax from cytosol to mitochondria [31], accelerates the protein degradation of pro-apoptotic Siva-1 [32,33], and increases the protein expression of Bcl-XL[34]. The effect of LPA on p21 in response to DNA damage is currently unknown. In some conditions, such as high-dose radiation for cancer treatment, blocking p53 (such as in p53 KO mice) in crypts of the small intestine leads to mitotic catastrophe, a type of cell death occurring during mitosis, as a result of DNA damage [35]. Inhibiting the p53-mediated p21 pathway is a major mechanism responsible for mitotic catastrophe in cells with unrepaired DNA. The p53-mediated cell cycle arrest pathway is hypothesized to offer cells a time window to process DNA repair in response to DNA damage. The numbers within parentheses indicate the sources of these findings. Detailed mechanisms related to apoptosis have been reviewed elsewhere [12-14].
Mentions: The p53 gene encodes protein containing 393 amino acid residues [25]. In non-stressed cells, p53 has a short half-life (~20 min), and its cellular concentration is thus maintained at a relatively low level [26]. When the cells are stressed by events from inside or (and) outside the cells, such as DNA damage induced by anticancer drug treatment or radiation therapy, p53 dissociates from its binding partner, MDM2, a critical negative regulator of p53, and is activated by post-translation modification [27]. As shown in Figure 2, p53 activation leads to G1-phase cell cycle arrest and DNA repair via transcriptional upregulation of related genes, such as p21 [36]. Successful DNA repair will allow cells to proceed with the cell cycle. Under DNA damage conditions, p53 also increases the expression of genes responsible for cell apoptosis, such as Bax [37] and p53 upregulated modulator of apoptosis (Puma) [38].

Bottom Line: In the human gastrointestinal tract, the functional mucosa of the small intestine has the highest capacity for absorption of nutrients and rapid proliferation rates, making it vulnerable to chemoradiotherapy.A traditional p53 inhibitor and two other molecules that exhibit strong protective effects on normal small intestinal epithelium during anticancer drug treatment and radiation therapy are introduced in this work.The objective of this review was to update current knowledge regarding potential mechanisms and targets that inhibit the side effects induced by chemoradiotherapy.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD 21210, USA.

ABSTRACT
In the human gastrointestinal tract, the functional mucosa of the small intestine has the highest capacity for absorption of nutrients and rapid proliferation rates, making it vulnerable to chemoradiotherapy. Recent understanding of the protective role of p53-mediated cell cycle arrest in the small intestinal mucosa has led researchers to explore new avenues to mitigate mucosal injury during cancer treatment. A traditional p53 inhibitor and two other molecules that exhibit strong protective effects on normal small intestinal epithelium during anticancer drug treatment and radiation therapy are introduced in this work. The objective of this review was to update current knowledge regarding potential mechanisms and targets that inhibit the side effects induced by chemoradiotherapy.

No MeSH data available.


Related in: MedlinePlus