Reference SummaryGao H, Proc Natl Acad Sci U S A 2004 Dec 7;101(49):17204-9
Title |
A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis. |
Authors |
Gao H; Ouyang X; Banach-Petrosky W; Borowsky AD; Lin Y; Kim M; Lee H; Shih WJ; Cardiff RD; Shen MM; Abate-Shen C |
Journal |
Proc Natl Acad Sci U S A |
Volume |
101 |
Issue |
49 |
Year |
2004 |
Pages |
17204-9 |
Abstract |
In human prostate cancer, the frequent down-regulation of p27(kip1) protein expression is correlated with poor clinical outcome, yet p27(kip1) rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating p27(kip1) function for prostate carcinogenesis in the context of a mouse modeling lacking the Nkx3.1 homeobox gene and the Pten tumor suppressor. Unexpectedly, we find that triple mutant mice heterozygous for a p27(kip1) null allele (Nkx3.1(+/- or -/-); Pten(+/-); p27(+/-)) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for p27(kip1) (Nkx3.1(+/- or -/-); Pten(+/-); p27(-/-)) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound p27(kip1) heterozygotes, but is down-regulated in the compound p27(kip1) homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct p27(kip1) gene doses, we show that prostate tumorigenicity depends on levels of p27(kip1) and that the consequences of p27(kip1) gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that p27(kip1) possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression. |
Links |
J:94720 – MGI References 15569926 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms/+ Ptentm1Rps/+ | Prostate gland - Dorsolateral lobe adenocarcinoma | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms | Prostate gland - Dorsolateral lobe prostatic intraepithelial neoplasia (PIN) | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Ptentm1Rps/+ | Prostate gland - Dorsolateral lobe prostatic intraepithelial neoplasia (PIN) | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Cdkn1btm1Ako/+ Ptentm1Rps/+ | Prostate gland - Dorsolateral lobe prostatic intraepithelial neoplasia (PIN) | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Nkx3-1tm1Mms Ptentm1Rps/+ | Prostate gland - Dorsolateral lobe prostatic intraepithelial neoplasia - high grade (HGPIN) | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Cdkn1btm1Ako Nkx3-1tm1Mms Ptentm1Rps/+ | Prostate gland - Dorsolateral lobe prostatic intraepithelial neoplasia - low grade (LGPIN) | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Cdkn1btm1Ako Ptentm1Rps/+ | Prostate gland - Dorsolateral lobe prostatic intraepithelial neoplasia - low grade (LGPIN) | Prostate gland - Dorsolateral lobe |
observed |
||
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms/+ Ptentm1Rps/+ | Prostate gland adenocarcinoma | Prostate gland |
observed |
||
| B6;129S-Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland hyperplasia | Prostate gland |
0 - 39 |
||
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland hyperplasia | Prostate gland |
0 - 19 |
||
| B6;129S-Cdkn1btm1Ako Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland hyperplasia | Prostate gland |
0 - 55 |
||
| B6;129S-Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - high grade (HGPIN) | Prostate gland |
33 - 73 |
||
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - high grade (HGPIN) | Prostate gland |
38 - 81 |
||
| B6;129S-Cdkn1btm1Ako Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - high grade (HGPIN) | Prostate gland |
19 - 100 |
||
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - high grade (HGPIN) | Prostate gland |
observed |
||
| B6;129S-Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - low grade (LGPIN) | Prostate gland |
27 - 28 |
||
| B6;129S-Cdkn1btm1Ako/+ Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - low grade (LGPIN) | Prostate gland |
19 - 43 |
||
| B6;129S-Cdkn1btm1Ako Nkx3-1tm1Mms/? Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - low grade (LGPIN) | Prostate gland |
0 - 26 |
||
| B6;129S-Cdkn1btm1Ako Nkx3-1tm1Mms Ptentm1Rps/+ | Prostate gland prostatic intraepithelial neoplasia - low grade (LGPIN) | Prostate gland |
observed |
||
| B6;129S | Prostate gland tumor | Prostate gland |
0 |