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Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2.

Ishikawa H, Carrasco D, Claudio E, Ryseck RP, Bravo R - J. Exp. Med. (1997)

Bottom Line: However, the physiological relevance of the p100 precursor as an IkappaB molecule has not been understood.Dramatic induction of nuclear kappaB-binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes.Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-kappaB complexes in various cell types and its absence cannot be efficiently compensated for by other IkappaB proteins.

View Article: PubMed Central - PubMed

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

ABSTRACT
The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-kappaB, the p100 precursor is believed to function as an inhibitor of Rel/NF-kappaB activity by cytoplasmic retention of Rel/NF-kappaB complexes, like other members of the IkappaB family. However, the physiological relevance of the p100 precursor as an IkappaB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-kappaB2 (p100(-/-)) had marked gastric hyperplasia, resulting in early postnatal death. p100(-/-) animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear kappaB-binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-kappaB complexes in various cell types and its absence cannot be efficiently compensated for by other IkappaB proteins.

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Histopathology of a  p100−/− mouse stomach. (A)  Stomach sections of 3-wk-old  wild-type (a and c) and p100−/−  (b and d) animals stained with  hematoxylin and eosin (original  magnification: 12.5-fold). As  shown in (b) the epithelial layer  (EL) was markedly thick,  whereas the gastric lumen (Lu)  was narrow in p100−/− mice.  Also, hyperkeratosis in cardiac  portion was evident in the  p100−/− stomach (d). (B) A section of a wild-type newborn  mouse was probed with nfkb2  cDNA, stained with carmine  red (b and c), and photographed  under dark (a and c) or light (b)  field illumination (original magnification: a, 4-fold; b and c, 25-fold). The nfkb2 transcript is expressed in thymus (Th) and in  the surface epithelium (c; arrows)  of the stomach (St).
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Figure 3: Histopathology of a p100−/− mouse stomach. (A) Stomach sections of 3-wk-old wild-type (a and c) and p100−/− (b and d) animals stained with hematoxylin and eosin (original magnification: 12.5-fold). As shown in (b) the epithelial layer (EL) was markedly thick, whereas the gastric lumen (Lu) was narrow in p100−/− mice. Also, hyperkeratosis in cardiac portion was evident in the p100−/− stomach (d). (B) A section of a wild-type newborn mouse was probed with nfkb2 cDNA, stained with carmine red (b and c), and photographed under dark (a and c) or light (b) field illumination (original magnification: a, 4-fold; b and c, 25-fold). The nfkb2 transcript is expressed in thymus (Th) and in the surface epithelium (c; arrows) of the stomach (St).

Mentions: The most striking histopathological alterations of p100−/− mice were detected in the stomach. By 2 wk of age the stomachs of p100−/− mice appeared smaller than those of the control littermates, and contained little food or milk (data not shown). The stomach showed a marked hyperplasia of the epithelial cell layer in the antrum with lymphocytic infiltration in the lamina propria and hyperkeratosis in the cardiac portion. In 3-wk-old p100−/− mice, the gastric abnormalities had increased in severity until the gastric lumen was mostly occluded, which most likely led to premature death of p100−/− mice (Fig. 3 A, compare a and c with b and d, respectively). The strong expression of the nfkb2 transcript found in the epithelial cell layer of the wild-type mouse stomach by in situ hybridization (Fig. 3 B, a and c) supports a physiological role for NF-κB2 in this area. Although young heterozygous mutant mice exhibited unremarkable histopathology, mild gastric hyperplasia was also observed in 10-mo-old p100+/− mice (data not shown).


Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2.

Ishikawa H, Carrasco D, Claudio E, Ryseck RP, Bravo R - J. Exp. Med. (1997)

Histopathology of a  p100−/− mouse stomach. (A)  Stomach sections of 3-wk-old  wild-type (a and c) and p100−/−  (b and d) animals stained with  hematoxylin and eosin (original  magnification: 12.5-fold). As  shown in (b) the epithelial layer  (EL) was markedly thick,  whereas the gastric lumen (Lu)  was narrow in p100−/− mice.  Also, hyperkeratosis in cardiac  portion was evident in the  p100−/− stomach (d). (B) A section of a wild-type newborn  mouse was probed with nfkb2  cDNA, stained with carmine  red (b and c), and photographed  under dark (a and c) or light (b)  field illumination (original magnification: a, 4-fold; b and c, 25-fold). The nfkb2 transcript is expressed in thymus (Th) and in  the surface epithelium (c; arrows)  of the stomach (St).
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Related In: Results  -  Collection

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Figure 3: Histopathology of a p100−/− mouse stomach. (A) Stomach sections of 3-wk-old wild-type (a and c) and p100−/− (b and d) animals stained with hematoxylin and eosin (original magnification: 12.5-fold). As shown in (b) the epithelial layer (EL) was markedly thick, whereas the gastric lumen (Lu) was narrow in p100−/− mice. Also, hyperkeratosis in cardiac portion was evident in the p100−/− stomach (d). (B) A section of a wild-type newborn mouse was probed with nfkb2 cDNA, stained with carmine red (b and c), and photographed under dark (a and c) or light (b) field illumination (original magnification: a, 4-fold; b and c, 25-fold). The nfkb2 transcript is expressed in thymus (Th) and in the surface epithelium (c; arrows) of the stomach (St).
Mentions: The most striking histopathological alterations of p100−/− mice were detected in the stomach. By 2 wk of age the stomachs of p100−/− mice appeared smaller than those of the control littermates, and contained little food or milk (data not shown). The stomach showed a marked hyperplasia of the epithelial cell layer in the antrum with lymphocytic infiltration in the lamina propria and hyperkeratosis in the cardiac portion. In 3-wk-old p100−/− mice, the gastric abnormalities had increased in severity until the gastric lumen was mostly occluded, which most likely led to premature death of p100−/− mice (Fig. 3 A, compare a and c with b and d, respectively). The strong expression of the nfkb2 transcript found in the epithelial cell layer of the wild-type mouse stomach by in situ hybridization (Fig. 3 B, a and c) supports a physiological role for NF-κB2 in this area. Although young heterozygous mutant mice exhibited unremarkable histopathology, mild gastric hyperplasia was also observed in 10-mo-old p100+/− mice (data not shown).

Bottom Line: However, the physiological relevance of the p100 precursor as an IkappaB molecule has not been understood.Dramatic induction of nuclear kappaB-binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes.Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-kappaB complexes in various cell types and its absence cannot be efficiently compensated for by other IkappaB proteins.

View Article: PubMed Central - PubMed

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

ABSTRACT
The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-kappaB, the p100 precursor is believed to function as an inhibitor of Rel/NF-kappaB activity by cytoplasmic retention of Rel/NF-kappaB complexes, like other members of the IkappaB family. However, the physiological relevance of the p100 precursor as an IkappaB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-kappaB2 (p100(-/-)) had marked gastric hyperplasia, resulting in early postnatal death. p100(-/-) animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear kappaB-binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-kappaB complexes in various cell types and its absence cannot be efficiently compensated for by other IkappaB proteins.

Show MeSH
Related in: MedlinePlus