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Int J Radiat Oncol Biol Phys. Author manuscript; available in PMC 2010 Feb 1.
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PMCID: PMC2631421

Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis



Radiation therapy for head and neck cancer causes adverse secondary side effects in the salivary glands and results in diminished quality of life for the patient. A previous in vivo study in parotid salivary glands demonstrated that targeted head and neck irradiation resulted in marked increases in phosphorylated p53 (serine18) and apoptosis, which was suppressed in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1).

Methods and Materials

Transgenic and knockout mouse models were exposed to irradiation and p53-mediated transcription, apoptosis, and salivary gland dysfunction were analyzed.


We report that the pro-apoptotic p53 target genes PUMA and Bax are induced in parotid salivary glands of mice at early time points following therapeutic radiation. This dose-dependent induction requires expression of p53 as no radiation-induced expression of PUMA and Bax is observed in p53−/− mice. Radiation also induces apoptosis in the parotid gland in a dose dependent manner, which is p53-dependent. Furthermore, expression of p53 is required for the acute and chronic loss of salivary function following irradiation. In contrast, p53−/− mice do not induce apoptosis and preserve salivary function after radiation exposure.


These results indicate that apoptosis in the salivary glands following therapeutic head and neck irradiation is mediated by p53 and corresponds to salivary gland dysfunction in vivo.


Therapeutic radiation is used for the treatment of head and neck cancer and commonly results in unwanted secondary side effects in normal salivary glands. These side effects include xerostomia, oral mucositis, and increased risk of periodontal disease resulting in diminished quality of life for these patients (1). Clinically, parotid salivary glands appear to be more radiosensitive than submandibular salivary glands (24), which has also been reported in animal models (5;6). Submandibular glands contribute approximately two-thirds of unstimulated saliva volume, whereas parotid glands contribute the majority of stimulated saliva volume (7;8).

Irradiation of the salivary glands causes a significant loss of acinar cells; however the mechanisms of this cellular attrition have been widely debated. Earlier work in a rat model quantified radiation-induced apoptosis by counting condensed nuclei and reported 2–3% apoptotic cells six hours after treatment with a broad range of doses (2.5–25 Gy) (9). The extent of apoptosis was not dose dependent and the authors concluded that the magnitude of apoptosis could not explain the significant loss of function (9). In contrast to rats, radiation-induced apoptosis is dose dependent in parotid glands of mice with significantly higher levels detected using immunohistochemistry against activated caspase-3 (5;10). The relevance of radiation-induced apoptosis to the overall physiological function of the salivary gland has not yet been elucidated.

Akt (protein kinase B) is a serine/threonine protein kinase that activates important survival signals in numerous tissues through a number of substrates (11). In primary salivary acinar cells, expression of the Akt substrate Murine Double Minute Clone 2 (MDM2) is required for suppression of DNA damage-induced apoptosis (10). Phosphorylation of MDM2 by Akt enhances its translocation to the nucleus, where it binds to p53 and targets p53 for degradation by the proteasome (12). DNA damage leads to p53 protein accumulation and transcriptional activation resulting in the induction of cell cycle arrest or apoptotic target genes (13). Among these p53 target genes are the pro-apoptotic Bcl-2 family members PUMA (p53 up-regulated modulator of apoptosis) and Bax (Bcl-2-associated X protein). PUMA interacts with Bax eventually leading to apoptosis (14) suggesting cooperative action of multiple p53 pro-apoptotic target genes (13). PERP (p53 apoptosis effector related to PMP-22), like Bax and PUMA, is a p53 target gene induced by DNA damage that may have pro-apoptotic effects (15). Elucidating the pathways activated following therapeutic radiation in the salivary glands will help determine the mechanism of dysfunction and potentially aid in the development of specific treatment options.

In this study, we observe a dose-dependent shift in PUMA and Bax mRNA expression in parotid salivary glands following irradiation in transgenic mice expressing a constitutively activated mutant of Akt1 (myr-Akt1) compared to FVB wildtype. In order to elucidate the specific role of p53 in salivary gland dysfunction, we used a genetically engineered mouse model containing a targeted deletion of p53 (p53−/−) (16). p53+/+ and p53+/− mice show a dose-dependent increase in transcription of pro-apoptotic genes (PUMA and Bax), which correlates with an increase in activated caspase-3. In contrast, p53−/− mice exhibit no change in expression of these pro-apoptotic genes or caspase-3 activation following irradiation. Apoptosis in the p53+/+ and p53+/− mice correlates with a significant decrease in stimulated salivary flow rates, indicative of salivary dysfunction, which is not observed in p53−/− mice. Our data support the hypothesis that p53 mediates an apoptotic pathology in normal salivary glands in vivo.



Myr-Akt1 transgenic mice under the control of the mouse mammary tumor virus promoter and maintained on an FVB background, were generated at the University of Colorado Health Sciences Center (17) and the salivary gland phenotype was described previously (10). p53 knockout mice were provided by Dr. Carla van den Berg (University of Texas at Austin), maintained on a Balb/c background, and genotyped using PCR (16). Primers used for genotyping were obtained from Integrated DNA Technologies (Coralville, IA).

Radiation Treatment

Four-week-old female FVB, myr-Akt1, or p53 mice from each genotype were anesthetized with avertin (0.4 to 0.6 mg/kg, intraperitoneally [i.p.]), and the head and neck region was exposed to radiation [Cobalt-60 Teletherapy unit from Atomic Energy of Canada Ltd Theratron-80] as previously described (10). Animals were maintained and treated in accordance with protocols approved by the University of Arizona IACUC.

RNA isolation and real-time RT-PCR

Parotid glands were removed from irradiated FVB, myr-Akt1, and p53 female mice (1, 2, or 5 Gy treatments) and RNA was isolated as previously described (10). 1 μg of RNA was reverse transcribed with a Super Script III kit according to manufacturer’s instructions (Invitrogen, Carlsbad, CA) and real-time RT-PCR was conducted in triplicate for each cDNA sample (3–5 mice per genotype per dose) with an iQ5 Real-Time PCR Detection System (BioRad, Hercules, CA). Forty cycles of PCR were performed (95°C for 15 seconds, 54°C for 30 seconds, 72°C for 30 seconds); fluorescence detection occurred during the 72°C step at each cycle. The data were analyzed using the 2−ΔΔCt method (18). Results were normalized to S15, which remains unchanged in response to treatment. Normalized values were plotted as relative fold over untreated wildtype. The following primers were purchased from Integrated DNA Technologies: S15 (10), PUMA (forward, 5′-CGT GTG ACC ACT GGC ATT CAT T-3′; reverse, 5′-ACA CAC ACA CAC ACA CAC ACA C-3′), PERP (19). QuantiTect Bax primers were purchased from Qiagen.


Tissues were fixed in 10% neutral buffered formalin for 24 hours, transferred to 70% ethanol, and embedded in paraffin. Tissue sections were cut to 4 μm and processed for standard staining with hematoxylin and eosin by the Histology Service Laboratory in the Department of Cell Biology and Anatomy at the University of Arizona.

Induction and quantification of apoptosis

Salivary glands were removed 24, 48, 72, and 96 hours post-irradiation and processed for histology as described above. Unstained tissue sections were processed for anti-activated caspase-3 immunohistochemistry as previously described (10). Tissue sections were observed by standard light microscopy, and photomicrographs were taken with a Leica DM5500 with a 4 megapixel Pursuit camera. Individual means for quantification of caspase-3 positive cells were determined by averaging the number of positive cells/total number of cells from a minimum of three fields of view/animal (2–3 mice per genotype per treatment; total cells counted ranged from 2,400 to 3,400 per field of view).

Saliva Collection

Mice were injected i.p. with 0.25 mg carbachol per kg body weight as previously described (10) on day 3 and 30 after radiation treatments. Saliva was collected from 8–10 mice/genotype/treatment on ice immediately following carbachol injection for 5 min into pre-weighed tubes and stored at −80°C.


Comparison of real-time RT-PCR and caspase-3 data was accomplished by a one-way ANOVA followed by a Bonferroni test with adjustment for the number of pairwise comparisons. Saliva flow rates were analyzed using a one-way ANOVA followed by Tukey’s multiple comparison test. Statistical analysis and graphical generation of data were done using GraphPad Prism software (San Diego, CA).


Pro-apoptotic p53 target genes are induced in parotid salivary glands following therapeutic radiation

A previous study in parotid salivary glands demonstrated that targeted head and neck irradiation resulted in marked increases in phosphorylated p53 (serine18) and apoptosis eight hours after treatment, which were inhibited in transgenic mice expressing myr-Akt1 (10). These data indicated that a rapid apoptotic response to DNA damage in the salivary glands may involve activation of p53 target genes. To investigate this we looked at the expression of two important pro-apoptotic transcriptional targets of p53 (PUMA and Bax) in parotid salivary glands following head and neck irradiation using the myr-Akt1 transgenic mouse line.

After irradiation, in both wildtype (FVB) and myr-Akt1 mice, PUMA expression is significantly up-regulated at 4 hours post treatment at doses of 2 and 5 Gy compared to genotype specific untreated controls (Fig. 1A). In myr-Akt1 transgenic mice eight hours after treatment, there appears to be a shift in the dose response curves for PUMA mRNA expression as evidenced by the significant reduction at 5 Gy compared to FVB wildtype (Fig. 1B). Induction of Bax follows a similar profile as PUMA at both time points (Fig. 1C,D). These data indicate a rapid induction of PUMA and Bax following irradiation that was modulated by myr-Akt1 eight hours after treatment. Reductions in radiation-induced p53 phosphorylation by Akt (10) correlates with the reductions in PUMA and Bax expression, which suggests a potential role for Akt in modulating p53 transcriptional activity in vivo.

Figure 1Figure 1Figure 1Figure 1
Induction of p53-dependent apoptotic genes in FVB wildtype and myr-Akt1 transgenic mice following radiation in vivo

Radiation-induced expression of PUMA and Bax depends on p53

To investigate the role of p53 in the induction of PUMA and Bax following radiation-induced DNA damage, we used a genetically engineered mouse model with a targeted deletion of p53 (16). p53+/+, p53+/−, and p53−/− mice were irradiated with 1, 2, or 5 Gy targeted to the head and neck region. Parotid salivary glands were collected 4 hours after treatment and expression of p53 pro-apoptotic genes was quantified by real-time RT-PCR. PUMA mRNA expression in irradiated p53+/+ and p53+/− mice is dose dependent with significant increases at 2 and 5 Gy compared to the respective untreated genotype (Fig. 2A). In both p53+/+ and +/− mice, maximal induction of PUMA is observed following 5 Gy, similar to the trend in FVB mice (Fig. 1A). PUMA expression in p53−/− mice appears to increase at 5 Gy; however, this is not significant due to slightly higher basal levels in untreated p53-/− mice. Bax mRNA expression follows a dose dependent trend in both p53+/+ and p53+/− mice with significant increases at all doses for p53+/+ and at 2 and 5 Gy for p53+/− (Fig. 2B). In contrast, there are no significant changes in expression of Bax following treatment in p53−/− mice.

Figure 2Figure 2
Induction of p53-dependent apoptotic genes in p53 mice following irradiation in vivo

PERP is not induced in the parotid salivary gland following irradiation

Induction of PERP following irradiation is p53-dependent and has been shown to contribute to apoptosis in neurons and thymocytes (15). In the salivary glands of mice treated with therapeutic radiation, there is no induction of PERP expression after four hours at any of the doses examined in the p53 genotypes (Fig. 3). This response is not mouse strain-dependent as there is no significant increase in PERP expression following radiation in p53+/+ mice maintained on a Balb/c genetic background or FVB wildtype mice (data not shown). These data do not provide evidence for involvement of PERP in the apoptotic response of parotid salivary glands to therapeutic radiation.

Figure 3
Analysis of PERP following irradiation in vivo

Radiation-induced apoptosis in the parotid gland is p53-dependent

In order to determine the necessity of p53 for radiation-induced apoptosis in the salivary glands, p53+/+, p53+/−, and p53−/− mice were exposed to 1, 2, 5, or 10 Gy radiation targeted to the head and neck region. As depicted in Figure 4A, we observe a dose-dependent increase in the number of apoptotic cells 24h after treatment in p53+/+ and +/− mice, as determined by activated caspase-3 positive cells, which is significant following 5 and 10 Gy. Interestingly, there is a significantly higher number of apoptotic cells in p53+/+ compared to p53+/− parotid salivary glands treated with 10 Gy. In contrast, p53−/− mice have no radiation-induced apoptosis at any dose of radiation we examined.

Figure 4Figure 4
Reduced apoptosis in p53−/− mice following head and neck irradiation

In order to determine the kinetics of salivary gland apoptosis, we evaluated caspase-3 activation at various time points after 5 Gy irradiation in all p53 genotypes (Fig. 4B). The peak number of apoptotic cells is observed between 24 and 48 hours in both p53+/+ and p53+/− mice. The number of apoptotic cells drops dramatically at 72 and 96 hours presumably due to clearance of these cells. No significant induction of apoptosis is observed in p53−/− mice at any of the time points. A majority (>95%) of the apoptotic cells counted for figures 4A and B are acinar cells. These data indicate that p53-independent apoptosis that has been observed in other tissues (20) is not prevalent in parotid salivary glands within 96 hours of treatment.

p53-dependent apoptosis affects salivary function

Acute and chronic reductions in salivary flow rates following radiation have been reported in rats (6;21), rhesus monkeys (22), and humans (23); however, the pathways to preserve function have remained elusive. In order to determine if salivary function is related to p53-dependent apoptosis, mice from all p53 genotypes were irradiated with 2 or 5 Gy and stimulated flow rates were determined on days 3 and 30. Radiation doses for functional studies were chosen based on clinical exposure of the salivary glands is typically kept below 2 Gy/day (24;25) and to correlate function with the induction of apoptosis (Fig. 4A).

Stimulated salivary flow rates are significantly reduced on day 3 in 2 Gy irradiated p53+/+ and p53+/− mice compared to genotype specific untreated mice (Fig. 5A). Remarkably, we observe similar decreases in stimulated salivary flow rates in p53+/+ mice after radiation with 5 Gy (Fig. 5B). The diminished salivary flow observed in our mouse model (~30–45%) is similar to previous studies using irradiated rats (~40–60%) (6;9;21). In contrast, p53−/− mice have no significant reduction in salivary flow at either dose of radiation examined. Early reductions in salivary flow rates therefore might be related to an apoptotic stress response mediated by p53 (Fig. 4B).

Figure 5Figure 5
Acute salivary gland dysfunction 3 days after radiation exposure

Mice were re-evaluated after 30 days to determine if salivary gland hypofunction persisted in response to radiation. Both p53+/+ and p53+/− mice have significantly decreased flow rates compared to untreated mice following exposure to either radiation dose (Fig. 6A,B). In contrast, p53−/− mice treated with therapeutic doses of radiation show little change in salivary flow rates. The significant reduction in saliva flow rate in p53+/+ and p53+/− mice at 2 and 5 Gy implies at least a 2 Gy threshold response to radiation in the salivary glands. These data suggest that expression of p53 is essential in the acute and chronic loss of salivary function following exposure to therapeutic radiation.

Figure 6Figure 6
Chronic salivary gland dysfunction 30 days after radiation exposure


Considerable uncertainty exists about the mechanisms of radiation-induced damage in salivary glands. Studies using a rat model reported significant decreases in salivary gland flow rates without a significant increase in apoptotic cells (9). However, our results indicate that modulation of the apoptotic response following therapeutic radiation preserves salivary gland function at both acute and chronic time points (Fig. 5 and and6).6). This suggests that radiation-induced apoptosis of salivary acinar cells correlates with salivary dysfunction. These data also indicate that apoptosis may have a more significant role in the impairment of function of the salivary glands following radiation exposure than previously reported. Interestingly, radiation-induced salivary gland dysfunction was not different between the two doses evaluated (Fig. 6; 2 and 5 Gy). This may indicate that there is a threshold of radiation sensitivity in mice at doses that parallel the salivary gland exposure in patients treated for head and neck cancer (i.e., 1.8–2.0 Gy/day) (24;25).

In our study we report that a significant induction of apoptosis (Fig. 4) occurs in parotid salivary glands exposed to radiation in mice expressing at least one allele of p53. The lack of apoptosis in parotid salivary glands and preservation of salivary flow in p53−/− mice within our study supports a role for p53 in an apoptotic pathology of the salivary glands. Our results concur with previous studies in other tissues (26;27), showing an inhibition of p53 may be beneficial in protecting radiosensitive tissues during therapeutic radiation treatment. These studies, along with our own, support the possibility that temporary inhibition of p53, through the use of molecules such as pifithrin-α, prior to irradiation may benefit patients through protection from adverse secondary side effects.

Regulation of p53’s functions in inducing apoptosis may lie in two different mechanisms: induction of apoptotic genes (13;28) or translocation to the mitochondria (29). While our study did not address p53 localization, this mechanism has been shown to occur in vivo (30) and occurs in the absence of transcription (31). A previous study in primary salivary acinar cells identified a critical role for the Akt/MDM2/p53 pathway in suppression of DNA damage-induced apoptosis (10). In mice expressing the myr-Akt1 transgene, we observe a dose-dependent shift in PUMA and Bax mRNA expression in parotid salivary glands following irradiation compared to FVB wildtype mice (Fig. 1B,D). This modulation of PUMA and Bax mRNA expression in myr-Akt1 parotid salivary glands is observed at the eight hour time point consistent with the reduced levels of phosphorylated p53 previously reported at this time point (10). In the p53+/+ and p53+/−mice, PUMA and Bax are significantly increased in the salivary glands following irradiation in a dose-dependent manner; however, there is no significant change in expression in p53−/− mice (Fig. 2). PUMA expression has also been shown to be regulated by p73, a homologue of p53 (32). This possibility could explain the slight (not significant) increase in PUMA mRNA expression in p53−/− parotid salivary glands at higher doses of radiation. As expected, the induction of pro-apoptotic genes resembles the apoptotic response in the parotid salivary glands following therapeutic radiation.

Alternatively, p53 has been shown to regulate the cellular processes of autophagy and senescence. Autophagy (‘self-eating’) can lead to enhanced cell survival or cell death depending on the tissue type or environmental stressor (33). In tumor models, autophagy is considered a secondary means of cell death when apoptosis has been blocked (34;35). Both activation and inhibition of p53 have been shown to induce autophagy (36;37); therefore, the implications to radiation-induced salivary gland dysfunction are unclear. Radiation-induced DNA damage can also result in p53-dependent senescence (38), which may contribute to the chronic, but not acute, loss of function in the salivary glands. It is likely that apoptosis, autophagy and senescence are present in irradiated salivary glands and may be not mutually exclusive. Future studies will be required to delineate the kinetics of these cellular processes.

Our data demonstrate that modulation of p53 expression (and thereby activation) directly correlates with preservation of salivary gland function. This is the first genetic evidence that links an intracellular pathway to potential mechanisms of radiation-induced salivary gland damage. A limitation of this study would be the use of a single dose of radiation considering that patients receive fractionated doses. By gaining an understanding of the p53-mediated pathways in salivary gland hypofunction we can continue to make strides to improve the overall quality of life of patients suffering from chronic secondary side effects attributed to therapeutic radiation.


p53 mice were a gift from Dr. Carla van den Berg (University of Texas at Austin). This work was supported in part by the NIH K22 DE 16096 and start-up funds from the University of Arizona.


Conflict of Interest Notification. Conflicts of interest do not exist for any of the authors.

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