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IkappaBalpha overexpression delays tumor formation in v-rel transgenic mice.

Carrasco D, Perez P, Lewin A, Bravo R - J. Exp. Med. (1997)

Bottom Line: Overexpression of IkappaBalpha in v-rel transgenic mice resulted in an extended survival, and the development of cutaneous T cell lymphomas of CD8(+)CD4(-) phenotype.These phenotypic alterations were associated with a dramatic reduction of p50/v-Rel, but not v-Rel/v-Rel nuclear DNA binding activity and an increased expression of the intercellular adhesion molecule 1.Our results indicate that v-Rel homodimers are active in transformation and that the capacity of v-Rel-containing complexes to escape the inhibitory effect of IkappaBalpha may be a key element in its transforming capability.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

ABSTRACT
We have previously shown that transgenic mice expressing the oncoprotein v-Rel under the control of a T cell-specific promoter develop T cell lymphomas. Tumor formation was correlated with the presence of p50/v-Rel and v-Rel/v-Rel nuclear kappaB-binding activity. Since experimental evidence has led to the suggestion of a potential tumor suppressor activity for IkappaBalpha, we have studied the role of IkappaBalpha in the transforming activity of v-Rel by overexpressing IkappaBalpha in v-rel transgenic mice. Overexpression of IkappaBalpha in v-rel transgenic mice resulted in an extended survival, and the development of cutaneous T cell lymphomas of CD8(+)CD4(-) phenotype. These phenotypic alterations were associated with a dramatic reduction of p50/v-Rel, but not v-Rel/v-Rel nuclear DNA binding activity and an increased expression of the intercellular adhesion molecule 1. Our results indicate that v-Rel homodimers are active in transformation and that the capacity of v-Rel-containing complexes to escape the inhibitory effect of IkappaBalpha may be a key element in its transforming capability.

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Overexpression of IκBα increases survival of v-rel transgenic  mice and changes the clinical expression. (A) Mortality curve. Deaths in  v-rel/ikba transgenic animals occurred at later times and were the result of  secondary opportunistic infection according to pathologic analysis and  microbiology. Autopsy, and histologic examination of v-rel/ikba transgenic mice revealed a less severe lymphomatous infiltrate than in v-rel  transgenic mice. n = 29 for v-rel 35, and n = 13 for v-rel/ikba. (B) T-cell  cutaneous lymphoma in v-rel/ikba double transgenic mice. All v-rel/ikba  transgenic mice developed skin lesions characterized by thickening and  exfoliative plaques. Arrow indicates a v-rel/ikba transgenic mouse; the  control mouse is an ikba transgenic littermate. (The lesions were never  observed in v-rel transgenic mice.)
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Figure 3: Overexpression of IκBα increases survival of v-rel transgenic mice and changes the clinical expression. (A) Mortality curve. Deaths in v-rel/ikba transgenic animals occurred at later times and were the result of secondary opportunistic infection according to pathologic analysis and microbiology. Autopsy, and histologic examination of v-rel/ikba transgenic mice revealed a less severe lymphomatous infiltrate than in v-rel transgenic mice. n = 29 for v-rel 35, and n = 13 for v-rel/ikba. (B) T-cell cutaneous lymphoma in v-rel/ikba double transgenic mice. All v-rel/ikba transgenic mice developed skin lesions characterized by thickening and exfoliative plaques. Arrow indicates a v-rel/ikba transgenic mouse; the control mouse is an ikba transgenic littermate. (The lesions were never observed in v-rel transgenic mice.)

Mentions: To investigate the consequences of the changes in κB binding activity in v-rel/ikba double transgenic mice, a colony of these animals was bred and their health status monitored over time in a nongerm-free environment (Fig. 3). The v-rel/ikba double transgenic mice presented a longer survival and appeared completely healthy for a longer period of time when compared with v-rel transgenic mice. The mortality curve demonstrates that high levels of IκBα extended the survival of v-rel transgenic mice (75% of v-rel transgenic mice succumbed before 25 wk of age, whereas 100% of the v-rel/ ikba double transgenic mice were unaffected at that time). Young v-rel/ikba double transgenic mice, between 3 and 10 wk old, appeared normal as assessed by habits, weight, posture, and histopathology. However, all v-rel/ikba double transgenic mice developed skin lesion in face, ears, tail, and feet after 15 wk of age. These lesions, characterized by loss of hair, thickening of the skin, and exfoliative plaques (Fig. 3 B) progressed slowly with no major compromise in the health status of the mice. Evaluation for a longer period of time revealed that v-rel/ikba double transgenic were susceptible to bacterial infections and that they succumbed due to secondary infections by pathogens that colonize the skin; antibiotic prophylactic treatment extended their survival for an additional 2–4 wk (data not shown). Autopsies of v-rel/ikba double transgenic mice did not reveal massive tumoral cell burden in lung, liver, lymph nodes, and spleen, indicating that in contrast to v-rel transgenic mice, massive tumor cellular infiltration was not the primary reason for organ failure in the double trangenic animals (17).


IkappaBalpha overexpression delays tumor formation in v-rel transgenic mice.

Carrasco D, Perez P, Lewin A, Bravo R - J. Exp. Med. (1997)

Overexpression of IκBα increases survival of v-rel transgenic  mice and changes the clinical expression. (A) Mortality curve. Deaths in  v-rel/ikba transgenic animals occurred at later times and were the result of  secondary opportunistic infection according to pathologic analysis and  microbiology. Autopsy, and histologic examination of v-rel/ikba transgenic mice revealed a less severe lymphomatous infiltrate than in v-rel  transgenic mice. n = 29 for v-rel 35, and n = 13 for v-rel/ikba. (B) T-cell  cutaneous lymphoma in v-rel/ikba double transgenic mice. All v-rel/ikba  transgenic mice developed skin lesions characterized by thickening and  exfoliative plaques. Arrow indicates a v-rel/ikba transgenic mouse; the  control mouse is an ikba transgenic littermate. (The lesions were never  observed in v-rel transgenic mice.)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198979&req=5

Figure 3: Overexpression of IκBα increases survival of v-rel transgenic mice and changes the clinical expression. (A) Mortality curve. Deaths in v-rel/ikba transgenic animals occurred at later times and were the result of secondary opportunistic infection according to pathologic analysis and microbiology. Autopsy, and histologic examination of v-rel/ikba transgenic mice revealed a less severe lymphomatous infiltrate than in v-rel transgenic mice. n = 29 for v-rel 35, and n = 13 for v-rel/ikba. (B) T-cell cutaneous lymphoma in v-rel/ikba double transgenic mice. All v-rel/ikba transgenic mice developed skin lesions characterized by thickening and exfoliative plaques. Arrow indicates a v-rel/ikba transgenic mouse; the control mouse is an ikba transgenic littermate. (The lesions were never observed in v-rel transgenic mice.)
Mentions: To investigate the consequences of the changes in κB binding activity in v-rel/ikba double transgenic mice, a colony of these animals was bred and their health status monitored over time in a nongerm-free environment (Fig. 3). The v-rel/ikba double transgenic mice presented a longer survival and appeared completely healthy for a longer period of time when compared with v-rel transgenic mice. The mortality curve demonstrates that high levels of IκBα extended the survival of v-rel transgenic mice (75% of v-rel transgenic mice succumbed before 25 wk of age, whereas 100% of the v-rel/ ikba double transgenic mice were unaffected at that time). Young v-rel/ikba double transgenic mice, between 3 and 10 wk old, appeared normal as assessed by habits, weight, posture, and histopathology. However, all v-rel/ikba double transgenic mice developed skin lesion in face, ears, tail, and feet after 15 wk of age. These lesions, characterized by loss of hair, thickening of the skin, and exfoliative plaques (Fig. 3 B) progressed slowly with no major compromise in the health status of the mice. Evaluation for a longer period of time revealed that v-rel/ikba double transgenic were susceptible to bacterial infections and that they succumbed due to secondary infections by pathogens that colonize the skin; antibiotic prophylactic treatment extended their survival for an additional 2–4 wk (data not shown). Autopsies of v-rel/ikba double transgenic mice did not reveal massive tumoral cell burden in lung, liver, lymph nodes, and spleen, indicating that in contrast to v-rel transgenic mice, massive tumor cellular infiltration was not the primary reason for organ failure in the double trangenic animals (17).

Bottom Line: Overexpression of IkappaBalpha in v-rel transgenic mice resulted in an extended survival, and the development of cutaneous T cell lymphomas of CD8(+)CD4(-) phenotype.These phenotypic alterations were associated with a dramatic reduction of p50/v-Rel, but not v-Rel/v-Rel nuclear DNA binding activity and an increased expression of the intercellular adhesion molecule 1.Our results indicate that v-Rel homodimers are active in transformation and that the capacity of v-Rel-containing complexes to escape the inhibitory effect of IkappaBalpha may be a key element in its transforming capability.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

ABSTRACT
We have previously shown that transgenic mice expressing the oncoprotein v-Rel under the control of a T cell-specific promoter develop T cell lymphomas. Tumor formation was correlated with the presence of p50/v-Rel and v-Rel/v-Rel nuclear kappaB-binding activity. Since experimental evidence has led to the suggestion of a potential tumor suppressor activity for IkappaBalpha, we have studied the role of IkappaBalpha in the transforming activity of v-Rel by overexpressing IkappaBalpha in v-rel transgenic mice. Overexpression of IkappaBalpha in v-rel transgenic mice resulted in an extended survival, and the development of cutaneous T cell lymphomas of CD8(+)CD4(-) phenotype. These phenotypic alterations were associated with a dramatic reduction of p50/v-Rel, but not v-Rel/v-Rel nuclear DNA binding activity and an increased expression of the intercellular adhesion molecule 1. Our results indicate that v-Rel homodimers are active in transformation and that the capacity of v-Rel-containing complexes to escape the inhibitory effect of IkappaBalpha may be a key element in its transforming capability.

Show MeSH
Related in: MedlinePlus