Reference SummaryTsai KY, Proc Natl Acad Sci U S A 2002 Dec 24;99(26):16865-70

Title

 ARF mutation accelerates pituitary tumor development in Rb+/- mice.

Authors

 Tsai KY; MacPherson D; Rubinson DA; Nikitin AY; Bronson R; Mercer KL; Crowley D; Jacks T

Journal

 Proc Natl Acad Sci U S A

Volume

 99

Issue

 26

Year

 2002

Pages

 16865-70

Abstract

 Mice heterozygous for the retinoblastoma (Rb) tumor suppressor gene develop pituitary and thyroid tumors with high penetrance. We demonstrate here that loss of the ARF tumor suppressor strongly accelerates intermediate lobe pituitary tumorigenesis in Rb heterozygous mice. These effects in the pituitary are greater than those conferred by p53 loss in that Rb+-;ARF-- mice display significantly more early atypical lesions than Rb+-; p53-- mice. Also, Rb+-;ARF-- compound mutants do not develop many of the novel tumors or precancerous lesions seen in Rb+-;p53-- compound mutants. Although complete loss of ARF expression is not obligatory for pituitary tumorigenesis in Rb+- mice, alterations of the ARF locus are observed in tumors from Rb+-;ARF+- mice, consistent with a selective advantage of ARF inactivation in this context. We conclude that inactivation of ARF acts more broadly than that of p53 in connecting abrogation of the Rb pathway to tumorigenesis.

Links

 J:81016 – MGI References
12486224 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6;129-Cdkn2atm1Cjs These mice were generated by mating mice heterozygous for Rb1tm1Tyj with mice homozygous for Cdkn2atm1Cjs, then intercrossing offspring to make compound mutants.
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Average survival 168 +/- 49 days (median = 168.5 days) for this cohort study (N=32). Virtually all mice died from intermediate lobe pituitary tumors.
These mice were generated by mating mice heterozygous for Rb1tm1Tyj with mice homozygous for Cdkn2atm1Cjs, then intercrossing offspring to make compound mutants.
B6;129-Cdkn2atm1Cjs/+ Rb1tm1Tyj/+ Median survival 262 days in this cohort study (N=13).
These mice were generated by mating mice heterozygous for Rb1tm1Tyj with mice homozygous for Cdkn2atm1Cjs, then intercrossing offspring to make compound mutants.
B6;129-Rb1tm1Tyj/+ Average survival 276 +/- 41 days (median = 277) for this cohort study (N=37).
Thes mice were used as control for a compound mutant study involving targeted mutations of Rb1, Trp53, and Cdkn2a.
B6;129-Rb1tm1Tyj/+ Trp53tm1Tyj These mice were generated by mating mice heterozygous for Rb1tm1Tyj with mice homozygous for Trp53tm1Tyj, then intercrossing offspring to make compound mutants.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129-Rb1tm1Tyj/+ Trp53tm1Tyj Lung hyperplasia Lung

observed
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Lung hyperplasia Lung

0
B6;129-Cdkn2atm1Cjs/+ Rb1tm1Tyj/+ Lung hyperplasia Lung

0
B6;129-Rb1tm1Tyj/+ Trp53tm1Tyj Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

observed
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

0
B6;129-Rb1tm1Tyj/+ Trp53tm1Tyj Pineal gland pineoblastoma Pineal gland

observed
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Pineal gland pineoblastoma Pineal gland

0
B6;129-Rb1tm1Tyj/+ Pituitary gland - Pars intermedia tumor Pituitary gland - Pars intermedia

very high
B6;129-Cdkn2atm1Cjs/+ Rb1tm1Tyj/+ Pituitary gland - Pars intermedia tumor Pituitary gland - Pars intermedia

observed
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Pituitary gland - Pars intermedia tumor Pituitary gland - Pars intermedia

very high
B6;129-Rb1tm1Tyj/+ Trp53tm1Tyj Pituitary gland lesion Pituitary gland

0 - 80
B6;129-Rb1tm1Tyj/+ Pituitary gland lesion Pituitary gland

0 - 60
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Pituitary gland lesion Pituitary gland

25 - 100
B6;129-Cdkn2atm1Cjs Pituitary gland lesion Pituitary gland

0
B6;129-Cdkn2atm1Cjs Pituitary gland tumor Pituitary gland

0
B6;129-Cdkn2atm1Cjs Rb1tm1Tyj/+ Thyroid gland - Medulla - C cell carcinoma Thyroid gland - Medulla - C cell

high
B6;129-Cdkn2atm1Cjs Thyroid gland - Medulla - C cell carcinoma Thyroid gland - Medulla - C cell

0