Reference SummaryPhilipp-Staheli J, Cancer Cell 2002 May;1(4):355-68

Title

 Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice.

Authors

 Philipp-Staheli J; Kim KH; Payne SR; Gurley KE; Liggitt D; Longton G; Kemp CJ

Journal

 Cancer Cell

Volume

 1

Issue

 4

Year

 2002

Pages

 355-68

Abstract

 Expression of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) is frequently reduced in human colorectal cancer, and this correlates with poor patient prognosis. To clarify the role of p27 in gastrointestinal (GI) cancer, we measured p27 expression, as well as the effect of germline deletion of p27, in 3 different mouse models of GI neoplasia. p27 expression was frequently reduced in GI tumors arising in 1,2-dimethylhydrazine (DMH) treated mice, and in Apc mutant Min/+ mice, but not in GI tumors arising in Smad3 mutant mice. Germline deletion of p27 resulted in accelerated tumor development and increased tumor cell proliferation in both DMH treated and Min/+ mice, but not in Smad3 mutant mice. p27 deficiency also led to increased adenoma to adenocarcinoma progression. These results indicate that reduction of p27 cooperates with mutations in Apc but not in Smad3 during GI tumorigenesis. Thus, tumor suppression by p27 is contingent on the specific oncogenic pathway that drives tumor development.

Links

 J:77135 – MGI References
12086850 – National Library of Medicine/PubMed

Strain Notes

Strain Note
129/Sv-Cdkn1btm1Mlf Smad3tm1Par 129/Sv-Smad3tm1Par/+ mice (129 substrain not specified) were obtained from J. Graff and crossed to 129.129S4(B6)-Cdkn1btm1Mlf/+ mice (N14) (129 substrain not specified). Progeny were intercrossed to generate these mice. The genetic background of these mice is primarily 129/Sv (substrain not specified) with contribution from (129X1/SvJ x 129S1/Sv)F1-Kitl+ and 129S4/SvJaeSor and possibly some C57BL/6.
Only 3/219 mice were of this genotype. Mice did not survive past 30 days of age. No further analysis done on genotype.
129/Sv-Cdkn1btm1Mlf/+ Smad3tm1Par 129/Sv-Smad3tm1Par/+ mice (129 substrain not specified) were obtained from J. Graff and crossed to 129.129S4(B6)-Cdkn1btm1Mlf/+ mice (N14) (129 substrain not specified). Progeny were intercrossed to generate these mice. The genetic background of these mice is primarily 129/Sv (substrain not specified) with contribution from (129X1/SvJ x 129S1/Sv)F1-Kitl+ and 129S4/SvJaeSor and possibly some C57BL/6.
129/Sv-Smad3tm1Par 129/Sv-Smad3tm1Par/+ mice (129 substrain not specified) were obtained from J. Graff and crossed to 129.129S4(B6)-Cdkn1btm1Mlf/+ mice (N14) (129 substrain not specified). Progeny were intercrossed to generate these mice. The genetic background of these mice is primarily 129/Sv (substrain not specified) with contribution from (129X1/SvJ x 129S1/Sv)F1-Kitl+ and 129S4/SvJaeSor and possibly some C57BL/6.
C57BL/6-ApcMin/+ C57BL/6J-ApcMin/+ mice were purchased from The Jackson Laboratory and crossed with B6.129S4-Cdkn1btm1Mlf/+ mice (N14) (homozygous for the C57BL/6 Pla2g2aMom1-s allele). Resulting offspring were intercrossed to generate these mice.
Littermates to compound ApcMin/+ Cdkn1b mutant study.
C57BL/6-ApcMin/+ Cdkn1btm1Mlf 100% of mice develop tumors by 10.5 weeks.
C57BL/6J-ApcMin/+ mice were purchased from The Jackson Laboratory and crossed with B6.129S4-Cdkn1btm1Mlf/+ mice (N14) (homozygous for the C57BL/6 Pla2g2aMom1-s allele). Resulting offspring were intercrossed to generate these mice.
Littermates to compound ApcMin/+ Cdkn1b mutant study.
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ 100% of mice develop tumors by 17.5 weeks.
C57BL/6J-ApcMin/+ mice were purchased from The Jackson Laboratory and crossed with B6.129S4-Cdkn1btm1Mlf/+ mice (N14) (homozygous for the C57BL/6 Pla2g2aMom1-s allele). Resulting offspring were intercrossed to generate these mice.
Littermates to compound ApcMin/+ Cdkn1b mutant study.
C57BL/6-Cdkn1btm1Mlf C57BL/6J-ApcMin/+ mice were purchased from The Jackson Laboratory and crossed with B6.129S4-Cdkn1btm1Mlf/+ mice (N14) (homozygous for the C57BL/6 Pla2g2aMom1-s allele). Resulting offspring were intercrossed to generate these mice.
Littermates to compound ApcMin/+ Cdkn1b mutant study.
NIH129 Littermates to Cdkn1b heterozygous and homozygous knockout mice.
NIH.129S4-Cdkn1btm1Mlf/+ mice (N7) were crossed with 129/Sv-Cdkn1btm1Mlf/+ mice (129 substrain not specified) to generate the mice used in this study (termed "F1" in the paper). The genetic background was approximately 50% NIH/OlaHsd and 50% 129/Sv (substrain not specified) with possibly some contribution from 129S4/SvJaeSor.
NIH129-Cdkn1btm1Mlf Littermates to Cdkn1b wild type and heterozygous mice.
NIH.129S4-Cdkn1btm1Mlf/+ mice (N7) were crossed with 129/Sv-Cdkn1btm1Mlf/+ mice (129 substrain not specified) to generate the mice used in this study (termed "F1" in the paper). The genetic background was approximately 50% NIH/OlaHsd and 50% 129/Sv (substrain not specified) with some contribution from 129S4/SvJaeSor.
Uterine and pituitary tumors also contributed to reduced survival in Cdkn1b deficient mice. Not specified whether heterozygote or homozygote mice.
NIH129-Cdkn1btm1Mlf/+ Littermates to Cdkn1b wild type and homozygous mice.
NIH.129S4-Cdkn1btm1Mlf/+ mice (N7) were crossed with 129/Sv-Cdkn1btm1Mlf/+ mice (129 substrain not specified) to generate the mice used in this study (termed "F1" in the paper). The genetic background was approximately 50% NIH/OlaHsd and 50% 129/Sv (substrain not specified) with some contribution from 129S4/SvJaeSor.
Uterine and pituitary tumors also contributed to reduced survival in Cdkn1b deficient mice. Not specified whether heterozygote or homozygote mice.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
129/Sv-Cdkn1btm1Mlf/+ Smad3tm1Par Intestine - Large Intestine - Cecum adenocarcinoma Intestine - Large Intestine - Cecum

observed
129/Sv-Smad3tm1Par Intestine - Large Intestine - Cecum adenocarcinoma Intestine - Large Intestine - Cecum

observed
129/Sv-Cdkn1btm1Mlf/+ Smad3tm1Par Intestine - Large Intestine - Cecum adenoma Intestine - Large Intestine - Cecum

observed
129/Sv-Smad3tm1Par Intestine - Large Intestine - Cecum adenoma Intestine - Large Intestine - Cecum

observed
NIH129-Cdkn1btm1Mlf Intestine - Large Intestine - Colon adenocarcinoma
  • 1,2-dimethylhydrazine (DMH)
 Intestine - Large Intestine - Colon

observed
NIH129-Cdkn1btm1Mlf/+ Intestine - Large Intestine - Colon adenocarcinoma
  • 1,2-dimethylhydrazine (DMH)
 Intestine - Large Intestine - Colon

observed
129/Sv-Cdkn1btm1Mlf/+ Smad3tm1Par Intestine - Large Intestine - Colon adenocarcinoma Intestine - Large Intestine - Colon

100
129/Sv-Smad3tm1Par Intestine - Large Intestine - Colon adenocarcinoma Intestine - Large Intestine - Colon

observed
NIH129-Cdkn1btm1Mlf Intestine - Large Intestine - Colon adenoma
  • 1,2-dimethylhydrazine (DMH)
 Intestine - Large Intestine - Colon

observed
NIH129-Cdkn1btm1Mlf/+ Intestine - Large Intestine - Colon adenoma
  • 1,2-dimethylhydrazine (DMH)
 Intestine - Large Intestine - Colon

observed
129/Sv-Cdkn1btm1Mlf/+ Smad3tm1Par Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed
129/Sv-Smad3tm1Par Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed
C57BL/6-ApcMin/+ Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed
C57BL/6-ApcMin/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed
NIH129 Intestine - Large Intestine adenocarcinoma
  • 1,2-dimethylhydrazine (DMH)
 Intestine - Large Intestine

observed
NIH129 Intestine - Large Intestine adenoma
  • 1,2-dimethylhydrazine (DMH)
 Intestine - Large Intestine

observed
129/Sv-Cdkn1btm1Mlf Smad3tm1Par Intestine - Large Intestine tumor Intestine - Large Intestine

0
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine - Small Intestine - Duodenum tumor Intestine - Small Intestine - Duodenum

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine - Small Intestine - Duodenum tumor Intestine - Small Intestine - Duodenum

observed
C57BL/6-ApcMin/+ Intestine - Small Intestine - Duodenum tumor Intestine - Small Intestine - Duodenum

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine - Small Intestine - Ileum tumor Intestine - Small Intestine - Ileum

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine - Small Intestine - Ileum tumor Intestine - Small Intestine - Ileum

observed
C57BL/6-ApcMin/+ Intestine - Small Intestine - Ileum tumor Intestine - Small Intestine - Ileum

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine - Small Intestine - Jejunum tumor Intestine - Small Intestine - Jejunum

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine - Small Intestine - Jejunum tumor Intestine - Small Intestine - Jejunum

observed
C57BL/6-ApcMin/+ Intestine - Small Intestine - Jejunum tumor Intestine - Small Intestine - Jejunum

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine adenoma Intestine

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine adenoma Intestine

observed
C57BL/6-ApcMin/+ Intestine adenoma Intestine

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine hyperplasia - adenomatous Intestine

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine hyperplasia - adenomatous Intestine

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf Intestine tumor Intestine

observed
C57BL/6-ApcMin/+ Cdkn1btm1Mlf/+ Intestine tumor Intestine

observed
C57BL/6-Cdkn1btm1Mlf Intestine tumor Intestine

0
C57BL/6-ApcMin/+ Intestine tumor Intestine

observed
NIH129-Cdkn1btm1Mlf/+ Intestine tumor
  • 1,2-dimethylhydrazine (DMH)
 Intestine

observed
129/Sv-Cdkn1btm1Mlf/+ Smad3tm1Par (Unspecified organ) tumor (Unspecified organ)

100
129/Sv-Smad3tm1Par (Unspecified organ) tumor (Unspecified organ)

observed
C57BL/6-ApcMin/+ (Unspecified organ) tumor (Unspecified organ)

100