Limits...
p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.

Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR, Miller FD - J. Cell Biol. (1998)

Bottom Line: NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax.Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited.Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.

ABSTRACT
Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pathway, is an essential component of both of these apoptotic signaling cascades. In cultured neonatal sympathetic neurons, p53 protein levels are elevated in response to both NGF withdrawal and p75NTR activation. NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. Direct stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bax are increased and the subsequent neuronal apoptosis can be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bax. Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited. Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

Show MeSH

Related in: MedlinePlus

E1B55K-mediated inhibition of p53 rescues sympathetic neuron apoptosis as induced by NGF withdrawal (A),  p75NTR activation (B), and activated MEKK (C–E). (A) p53  and NGF withdrawal-induced apoptosis. Sympathetic neurons  were infected in parallel with recombinant adenovirus expressing  E1B55K, the mutant E1B55K A262, or β-galactosidase (LacZ) at  titers of 100 or 500 moi and NGF was withdrawn from the media  2 d later. After 48 h, cell survival was measured by MTT assays. 0  NGF represents uninfected sympathetic neurons that were also  withdrawn from NGF, whereas 10 NGF represents uninfected  sympathetic neurons maintained in the presence of 10 ng/ml NGF  for the course of the experiment. Results are those obtained in a  representative experiment performed in triplicate, and represent  the mean ± the standard error. Similar results were obtained in  five separate experiments. ***Indicates those values that are significantly different from the 0 NGF control (P < 0.005). Note  that only those neurons transduced with E1B55K were rescued  from NGF withdrawal-induced apoptosis. (B) p53 and p75-induced apoptosis. Sympathetic neurons were infected with recombinant adenovirus expressing E1B55K or the mutant E1B55K  A262 at a titer of 500 moi and 2 d later were switched into 50 mM  KCl (KCL+E1B55K and KCL+A262) or 50 mM KCl plus 100  ng/ml BDNF (KCL+BDNF+E1B55K and KCL+BDNF+  A262). As controls, uninfected neurons were switched into 50 mM  KCl (50 KCL), into 50 mM KCl plus 100 ng/ml BDNF  (KCL+BDNF), or were withdrawn from NGF (0 NGF). After  48 h, cell survival was measured using MTT assays. Results are  those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Similar results  were obtained in four separate experiments. ***Indicates those  values that are significantly different from 50 mM KCl alone, and  (***) indicates those values amongst the points that received  BDNF that are significantly different from KCL+BDNF (P <  0.005). Note that, as previously reported (Bamji et al., 1998),  BDNF reduces neuronal survival in the presence of KCl, and that  E1B55K but not A262 is able to completely rescue this BDNF- mediated apoptosis. (C) MEKK1-induced apoptosis. Sympathetic  neurons were infected with recombinant adenovirus expressing  activated MEKK1 or β-galactosidase (LacZ) at concentrations of  20 to 200 moi, and were maintained in 20 ng/ml NGF for 4 d after  infection. As controls, uninfected neurons were maintained for  the entire experiment in 20 ng/ml NGF. Cell survival was measured using MTT assays, and results are those obtained in a representative experiment performed in triplicate, and represent the  mean ± standard error. Similar results were obtained in 4 separate experiments. **Indicates those values that are significantly  different between MEKK1 and the β-galactosidase control at a  given moi (P < 0.005). Note that activated MEKK1 decreases  sympathetic neuron survival in a concentration-dependent fashion. (D) p53 and MEKK1-induced apoptosis. Sympathetic neurons  were infected with 50 moi of MEKK1 plus 500 moi of E1B55K  (MEKK +E1B55K), A262 (MEKK + A262) or β-galactosidase  (MEKK + LacZ), were maintained in 20 ng/ml NGF for 4 d after  infection, and survival was then measured using MTT assays. As  further controls, neurons were infected with 50 moi β-galactosidase virus (20 NGF+ 50 LacZ) for the same time period, or were  withdrawn from NGF for the final two days. Results are those obtained in a representative experiment performed in triplicate, and  represent the mean ± standard error. Results are normalized so  that 0 NGF is 0% survival, and 20 ng/ml NGF plus 50 moi β-galactosidase (20 NGF+ 50 LacZ) is 100% survival. Similar results  were obtained in three separate experiments. ***Indicates that  E1B55K significantly rescues MEKK1-induced killing of sympathetic neurons (P < 0.005). (E) p53 in JNK-Bax cell death  pathway. Sympathetic neurons were infected with 50 moi of the  activated MEKK1 adenovirus (50 MEKK) plus or minus 50 moi  Bcl-xl (MEKK+ Bcl-xl), 500 moi E1B55K (MEKK+ E1B55K)  or 500 moi A262 (MEKK + A262) adenoviruses. As a control,  neurons were infected with 50 moi β-galactosidase adenovirus  (50 LacZ). 4 d after the initial infection, during which time neurons were maintained in 10 ng/ml NGF, survival was measured  using MTT assays. Results are those obtained in a representative  experiment performed in triplicate, and represent the mean ±  standard error. Results are normalized so that 0 NGF is 0%, and  10 ng/ml NGF plus 50 moi β-galactosidase adenovirus is 100%  survival. ***Indicates those values that are significantly different  from MEKK alone (P < 0.005).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2132983&req=5

Figure 2: E1B55K-mediated inhibition of p53 rescues sympathetic neuron apoptosis as induced by NGF withdrawal (A), p75NTR activation (B), and activated MEKK (C–E). (A) p53 and NGF withdrawal-induced apoptosis. Sympathetic neurons were infected in parallel with recombinant adenovirus expressing E1B55K, the mutant E1B55K A262, or β-galactosidase (LacZ) at titers of 100 or 500 moi and NGF was withdrawn from the media 2 d later. After 48 h, cell survival was measured by MTT assays. 0 NGF represents uninfected sympathetic neurons that were also withdrawn from NGF, whereas 10 NGF represents uninfected sympathetic neurons maintained in the presence of 10 ng/ml NGF for the course of the experiment. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± the standard error. Similar results were obtained in five separate experiments. ***Indicates those values that are significantly different from the 0 NGF control (P < 0.005). Note that only those neurons transduced with E1B55K were rescued from NGF withdrawal-induced apoptosis. (B) p53 and p75-induced apoptosis. Sympathetic neurons were infected with recombinant adenovirus expressing E1B55K or the mutant E1B55K A262 at a titer of 500 moi and 2 d later were switched into 50 mM KCl (KCL+E1B55K and KCL+A262) or 50 mM KCl plus 100 ng/ml BDNF (KCL+BDNF+E1B55K and KCL+BDNF+ A262). As controls, uninfected neurons were switched into 50 mM KCl (50 KCL), into 50 mM KCl plus 100 ng/ml BDNF (KCL+BDNF), or were withdrawn from NGF (0 NGF). After 48 h, cell survival was measured using MTT assays. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Similar results were obtained in four separate experiments. ***Indicates those values that are significantly different from 50 mM KCl alone, and (***) indicates those values amongst the points that received BDNF that are significantly different from KCL+BDNF (P < 0.005). Note that, as previously reported (Bamji et al., 1998), BDNF reduces neuronal survival in the presence of KCl, and that E1B55K but not A262 is able to completely rescue this BDNF- mediated apoptosis. (C) MEKK1-induced apoptosis. Sympathetic neurons were infected with recombinant adenovirus expressing activated MEKK1 or β-galactosidase (LacZ) at concentrations of 20 to 200 moi, and were maintained in 20 ng/ml NGF for 4 d after infection. As controls, uninfected neurons were maintained for the entire experiment in 20 ng/ml NGF. Cell survival was measured using MTT assays, and results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Similar results were obtained in 4 separate experiments. **Indicates those values that are significantly different between MEKK1 and the β-galactosidase control at a given moi (P < 0.005). Note that activated MEKK1 decreases sympathetic neuron survival in a concentration-dependent fashion. (D) p53 and MEKK1-induced apoptosis. Sympathetic neurons were infected with 50 moi of MEKK1 plus 500 moi of E1B55K (MEKK +E1B55K), A262 (MEKK + A262) or β-galactosidase (MEKK + LacZ), were maintained in 20 ng/ml NGF for 4 d after infection, and survival was then measured using MTT assays. As further controls, neurons were infected with 50 moi β-galactosidase virus (20 NGF+ 50 LacZ) for the same time period, or were withdrawn from NGF for the final two days. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Results are normalized so that 0 NGF is 0% survival, and 20 ng/ml NGF plus 50 moi β-galactosidase (20 NGF+ 50 LacZ) is 100% survival. Similar results were obtained in three separate experiments. ***Indicates that E1B55K significantly rescues MEKK1-induced killing of sympathetic neurons (P < 0.005). (E) p53 in JNK-Bax cell death pathway. Sympathetic neurons were infected with 50 moi of the activated MEKK1 adenovirus (50 MEKK) plus or minus 50 moi Bcl-xl (MEKK+ Bcl-xl), 500 moi E1B55K (MEKK+ E1B55K) or 500 moi A262 (MEKK + A262) adenoviruses. As a control, neurons were infected with 50 moi β-galactosidase adenovirus (50 LacZ). 4 d after the initial infection, during which time neurons were maintained in 10 ng/ml NGF, survival was measured using MTT assays. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Results are normalized so that 0 NGF is 0%, and 10 ng/ml NGF plus 50 moi β-galactosidase adenovirus is 100% survival. ***Indicates those values that are significantly different from MEKK alone (P < 0.005).

Mentions: To determine whether this increase in p53 protein levels was an essential component of the apoptotic cascade that follows NGF withdrawal, we took advantage of the adenoviral E1B55K protein, which functionally ablates p53 (Yew et al., 1992). Specifically, neonatal sympathetic neurons were cultured for 3–4 d in 50 ng/ml NGF, and then were infected with one of two recombinant, replication-defective adenoviruses; one of these adenoviruses expressed E1B55K while the second expressed a mutant E1B55K protein (A262) that is defective in its ability to bind and ablate p53 (Yew et al., 1990). As a further control, neurons were infected with a similar moi of recombinant adenovirus expressing β-galactosidase (Slack et al., 1996). 2 d after viral infection, neurons were washed free of NGF and 2 d later, neuronal survival was measured using MTT assays (Fig. 2 A). These experiments demonstrated that E1B55K, but not the E1B55K mutant A262 or β-galactosidase, was able to rescue sympathetic neurons from apoptosis. In 5 independent experiments, E1B55K rescued 49% (100 moi) and 63% (500 moi) of the neurons relative to those kept alive in 10 ng/ml NGF, increases which were highly significant (P < 0.005 in both cases). In none of these experiments did either the A262 or β-galactosidase virus have a significant effect on neuronal survival (Fig. 2 A).


p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.

Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR, Miller FD - J. Cell Biol. (1998)

E1B55K-mediated inhibition of p53 rescues sympathetic neuron apoptosis as induced by NGF withdrawal (A),  p75NTR activation (B), and activated MEKK (C–E). (A) p53  and NGF withdrawal-induced apoptosis. Sympathetic neurons  were infected in parallel with recombinant adenovirus expressing  E1B55K, the mutant E1B55K A262, or β-galactosidase (LacZ) at  titers of 100 or 500 moi and NGF was withdrawn from the media  2 d later. After 48 h, cell survival was measured by MTT assays. 0  NGF represents uninfected sympathetic neurons that were also  withdrawn from NGF, whereas 10 NGF represents uninfected  sympathetic neurons maintained in the presence of 10 ng/ml NGF  for the course of the experiment. Results are those obtained in a  representative experiment performed in triplicate, and represent  the mean ± the standard error. Similar results were obtained in  five separate experiments. ***Indicates those values that are significantly different from the 0 NGF control (P < 0.005). Note  that only those neurons transduced with E1B55K were rescued  from NGF withdrawal-induced apoptosis. (B) p53 and p75-induced apoptosis. Sympathetic neurons were infected with recombinant adenovirus expressing E1B55K or the mutant E1B55K  A262 at a titer of 500 moi and 2 d later were switched into 50 mM  KCl (KCL+E1B55K and KCL+A262) or 50 mM KCl plus 100  ng/ml BDNF (KCL+BDNF+E1B55K and KCL+BDNF+  A262). As controls, uninfected neurons were switched into 50 mM  KCl (50 KCL), into 50 mM KCl plus 100 ng/ml BDNF  (KCL+BDNF), or were withdrawn from NGF (0 NGF). After  48 h, cell survival was measured using MTT assays. Results are  those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Similar results  were obtained in four separate experiments. ***Indicates those  values that are significantly different from 50 mM KCl alone, and  (***) indicates those values amongst the points that received  BDNF that are significantly different from KCL+BDNF (P <  0.005). Note that, as previously reported (Bamji et al., 1998),  BDNF reduces neuronal survival in the presence of KCl, and that  E1B55K but not A262 is able to completely rescue this BDNF- mediated apoptosis. (C) MEKK1-induced apoptosis. Sympathetic  neurons were infected with recombinant adenovirus expressing  activated MEKK1 or β-galactosidase (LacZ) at concentrations of  20 to 200 moi, and were maintained in 20 ng/ml NGF for 4 d after  infection. As controls, uninfected neurons were maintained for  the entire experiment in 20 ng/ml NGF. Cell survival was measured using MTT assays, and results are those obtained in a representative experiment performed in triplicate, and represent the  mean ± standard error. Similar results were obtained in 4 separate experiments. **Indicates those values that are significantly  different between MEKK1 and the β-galactosidase control at a  given moi (P < 0.005). Note that activated MEKK1 decreases  sympathetic neuron survival in a concentration-dependent fashion. (D) p53 and MEKK1-induced apoptosis. Sympathetic neurons  were infected with 50 moi of MEKK1 plus 500 moi of E1B55K  (MEKK +E1B55K), A262 (MEKK + A262) or β-galactosidase  (MEKK + LacZ), were maintained in 20 ng/ml NGF for 4 d after  infection, and survival was then measured using MTT assays. As  further controls, neurons were infected with 50 moi β-galactosidase virus (20 NGF+ 50 LacZ) for the same time period, or were  withdrawn from NGF for the final two days. Results are those obtained in a representative experiment performed in triplicate, and  represent the mean ± standard error. Results are normalized so  that 0 NGF is 0% survival, and 20 ng/ml NGF plus 50 moi β-galactosidase (20 NGF+ 50 LacZ) is 100% survival. Similar results  were obtained in three separate experiments. ***Indicates that  E1B55K significantly rescues MEKK1-induced killing of sympathetic neurons (P < 0.005). (E) p53 in JNK-Bax cell death  pathway. Sympathetic neurons were infected with 50 moi of the  activated MEKK1 adenovirus (50 MEKK) plus or minus 50 moi  Bcl-xl (MEKK+ Bcl-xl), 500 moi E1B55K (MEKK+ E1B55K)  or 500 moi A262 (MEKK + A262) adenoviruses. As a control,  neurons were infected with 50 moi β-galactosidase adenovirus  (50 LacZ). 4 d after the initial infection, during which time neurons were maintained in 10 ng/ml NGF, survival was measured  using MTT assays. Results are those obtained in a representative  experiment performed in triplicate, and represent the mean ±  standard error. Results are normalized so that 0 NGF is 0%, and  10 ng/ml NGF plus 50 moi β-galactosidase adenovirus is 100%  survival. ***Indicates those values that are significantly different  from MEKK alone (P < 0.005).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132983&req=5

Figure 2: E1B55K-mediated inhibition of p53 rescues sympathetic neuron apoptosis as induced by NGF withdrawal (A), p75NTR activation (B), and activated MEKK (C–E). (A) p53 and NGF withdrawal-induced apoptosis. Sympathetic neurons were infected in parallel with recombinant adenovirus expressing E1B55K, the mutant E1B55K A262, or β-galactosidase (LacZ) at titers of 100 or 500 moi and NGF was withdrawn from the media 2 d later. After 48 h, cell survival was measured by MTT assays. 0 NGF represents uninfected sympathetic neurons that were also withdrawn from NGF, whereas 10 NGF represents uninfected sympathetic neurons maintained in the presence of 10 ng/ml NGF for the course of the experiment. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± the standard error. Similar results were obtained in five separate experiments. ***Indicates those values that are significantly different from the 0 NGF control (P < 0.005). Note that only those neurons transduced with E1B55K were rescued from NGF withdrawal-induced apoptosis. (B) p53 and p75-induced apoptosis. Sympathetic neurons were infected with recombinant adenovirus expressing E1B55K or the mutant E1B55K A262 at a titer of 500 moi and 2 d later were switched into 50 mM KCl (KCL+E1B55K and KCL+A262) or 50 mM KCl plus 100 ng/ml BDNF (KCL+BDNF+E1B55K and KCL+BDNF+ A262). As controls, uninfected neurons were switched into 50 mM KCl (50 KCL), into 50 mM KCl plus 100 ng/ml BDNF (KCL+BDNF), or were withdrawn from NGF (0 NGF). After 48 h, cell survival was measured using MTT assays. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Similar results were obtained in four separate experiments. ***Indicates those values that are significantly different from 50 mM KCl alone, and (***) indicates those values amongst the points that received BDNF that are significantly different from KCL+BDNF (P < 0.005). Note that, as previously reported (Bamji et al., 1998), BDNF reduces neuronal survival in the presence of KCl, and that E1B55K but not A262 is able to completely rescue this BDNF- mediated apoptosis. (C) MEKK1-induced apoptosis. Sympathetic neurons were infected with recombinant adenovirus expressing activated MEKK1 or β-galactosidase (LacZ) at concentrations of 20 to 200 moi, and were maintained in 20 ng/ml NGF for 4 d after infection. As controls, uninfected neurons were maintained for the entire experiment in 20 ng/ml NGF. Cell survival was measured using MTT assays, and results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Similar results were obtained in 4 separate experiments. **Indicates those values that are significantly different between MEKK1 and the β-galactosidase control at a given moi (P < 0.005). Note that activated MEKK1 decreases sympathetic neuron survival in a concentration-dependent fashion. (D) p53 and MEKK1-induced apoptosis. Sympathetic neurons were infected with 50 moi of MEKK1 plus 500 moi of E1B55K (MEKK +E1B55K), A262 (MEKK + A262) or β-galactosidase (MEKK + LacZ), were maintained in 20 ng/ml NGF for 4 d after infection, and survival was then measured using MTT assays. As further controls, neurons were infected with 50 moi β-galactosidase virus (20 NGF+ 50 LacZ) for the same time period, or were withdrawn from NGF for the final two days. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Results are normalized so that 0 NGF is 0% survival, and 20 ng/ml NGF plus 50 moi β-galactosidase (20 NGF+ 50 LacZ) is 100% survival. Similar results were obtained in three separate experiments. ***Indicates that E1B55K significantly rescues MEKK1-induced killing of sympathetic neurons (P < 0.005). (E) p53 in JNK-Bax cell death pathway. Sympathetic neurons were infected with 50 moi of the activated MEKK1 adenovirus (50 MEKK) plus or minus 50 moi Bcl-xl (MEKK+ Bcl-xl), 500 moi E1B55K (MEKK+ E1B55K) or 500 moi A262 (MEKK + A262) adenoviruses. As a control, neurons were infected with 50 moi β-galactosidase adenovirus (50 LacZ). 4 d after the initial infection, during which time neurons were maintained in 10 ng/ml NGF, survival was measured using MTT assays. Results are those obtained in a representative experiment performed in triplicate, and represent the mean ± standard error. Results are normalized so that 0 NGF is 0%, and 10 ng/ml NGF plus 50 moi β-galactosidase adenovirus is 100% survival. ***Indicates those values that are significantly different from MEKK alone (P < 0.005).
Mentions: To determine whether this increase in p53 protein levels was an essential component of the apoptotic cascade that follows NGF withdrawal, we took advantage of the adenoviral E1B55K protein, which functionally ablates p53 (Yew et al., 1992). Specifically, neonatal sympathetic neurons were cultured for 3–4 d in 50 ng/ml NGF, and then were infected with one of two recombinant, replication-defective adenoviruses; one of these adenoviruses expressed E1B55K while the second expressed a mutant E1B55K protein (A262) that is defective in its ability to bind and ablate p53 (Yew et al., 1990). As a further control, neurons were infected with a similar moi of recombinant adenovirus expressing β-galactosidase (Slack et al., 1996). 2 d after viral infection, neurons were washed free of NGF and 2 d later, neuronal survival was measured using MTT assays (Fig. 2 A). These experiments demonstrated that E1B55K, but not the E1B55K mutant A262 or β-galactosidase, was able to rescue sympathetic neurons from apoptosis. In 5 independent experiments, E1B55K rescued 49% (100 moi) and 63% (500 moi) of the neurons relative to those kept alive in 10 ng/ml NGF, increases which were highly significant (P < 0.005 in both cases). In none of these experiments did either the A262 or β-galactosidase virus have a significant effect on neuronal survival (Fig. 2 A).

Bottom Line: NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax.Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited.Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.

ABSTRACT
Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pathway, is an essential component of both of these apoptotic signaling cascades. In cultured neonatal sympathetic neurons, p53 protein levels are elevated in response to both NGF withdrawal and p75NTR activation. NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. Direct stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bax are increased and the subsequent neuronal apoptosis can be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bax. Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited. Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

Show MeSH
Related in: MedlinePlus