Reference SummaryPhilipp-Staheli J, Oncogene 2004 Jan 29;23(4):905-13

Title

Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development.

Authors

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

Journal

Oncogene

Volume

23

Issue

4

Year

2004

Pages

905-13

Abstract

Mutations in p53 and reduced expression of the Cdk inhibitor p27Kip1 are frequently observed in a wide variety of human cancers, but it is not known whether alterations in these tumor suppressors interact to influence tumor progression. To address this, we measured tumor latency and spectrum in p53 and p27 single and compound mutant mice. p53-/- (null) mice developed T-cell lymphomas and soft-tissue sarcomas, while p27-/- mice developed adenomas of the pituitary and lung, but with much longer latency. The latency for tumor development in p53-/- p27-/- and p53-/- p27+/- compound mutant mice was significantly reduced, by 15-30%, compared to single mutant p53-/- mice. The tumor spectrum in the compound mutants was similar to that of p53-/- mice, and additional tumors of diverse histotypes. In tumors from p53-/- mice, p27 protein levels were reduced to a greater extent than were mRNA levels, indicating that p27 is downregulated in tumors at the transcriptional as well as post-transcriptional levels. In contrast, mice deficient in another Cdk inhibitor p21Cip1, which is also a transcriptional target and effector of p53, showed only a marginal increase in tumor predisposition in response to ENU treatment. Thus, downregulation of p27 is a common feature in p53-/- tumors. Germline deletion of one or both alleles of p27 accelerates tumor development and associated mortality in p53-/- mice, indicating potent synergy between loss of p27 and p53. Although p21 is functionally similar to both p53 and p27, it plays a lesser role in tumor suppression. These results further highlight the highly cooperative nature of p27 and its central role in tumor suppression.

Links

J:87536 – Mouse Genome Informatics
14647411 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Cdkn1btm1Mlf Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

very low

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

very low

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Adrenal gland tumor Adrenal gland

very low

NIH.129S6-Cdkn1atm1Led Blood vessel hemangiosarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Blood vessel

7.4

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd CNS - Brain - Ependyma tumor CNS - Brain - Ependyma

very low

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd CNS - Brain - Undifferentiated cell glioblastoma CNS - Brain - Undifferentiated cell

very low

NIH.129S6-Cdkn1atm1Led Connective tissue myxoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Skin - Dermis

11

[not specified]-Cdkn1btm1Mlf Eye - Harderian gland adenoma Eye - Harderian gland

very low

NIH.129S6-Cdkn1atm1Led Intestine tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Intestine

11

NIH.129S6-Cdkn1atm1Led/+ Intestine tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Intestine

0

NIH Intestine tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Intestine

7.7

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Kidney transitional cell carcinoma Kidney

very low

STOCK Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

STOCK Cdkn1btm1Mlf Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

C57BL/6-Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

C57BL/6-Cdkn1btm1Mlf Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

C57BL/6-Cdkn1btm1Mlf/+ Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

[not specified]-Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

[not specified]-Cdkn1btm1Mlf Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

very low

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

high

STOCK Cdkn1btm1Mlf/+ Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte tumor Leukocyte - Lymphocyte - T-lymphocyte

high

NIH.129S6-Cdkn1atm1Led Leukocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte

11

NIH.129S6-Cdkn1atm1Led/+ Leukocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte

34

NIH Leukocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte

31

NIH.129S6-Cdkn1atm1Led Liver hepatocellular adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Liver

19

NIH.129S6-Cdkn1atm1Led/+ Liver tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Liver

10

NIH Liver tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Liver

3.8

[not specified]-Cdkn1btm1Mlf Lung adenocarcinoma Lung

very low

[not specified]-Cdkn1btm1Mlf Lung adenoma Lung

very low

NIH.129S6-Cdkn1atm1Led Lung tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

100

NIH.129S6-Cdkn1atm1Led/+ Lung tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

100

NIH Lung tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

100

[not specified]-Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

moderate

[not specified]-Cdkn1btm1Mlf Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

0

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

low

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

moderate

NIH.129S6-Cdkn1atm1Led Mesodermal cell/mesoblast sarcoma - poorly differentiated
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Mesodermal cell/mesoblast

7.4

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd Neuroblast neuroblastoma Neuroblast

very low

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Pericyte hemangiopericytoma Pericyte

very low

[not specified]-Cdkn1btm1Mlf Pituitary gland adenoma Pituitary gland

low

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Stomach carcinoma - poorly differentiated Stomach

very low

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd Testis - Seminiferous tubules - Sertoli cell tumor Testis - Seminiferous tubules - Sertoli cell

very low

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd Testis - Seminiferous tubules - Sertoli cell tumor Testis - Seminiferous tubules - Sertoli cell

very low

NIH.129S6-Cdkn1atm1Led Urinary bladder transitional cell carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Urinary bladder

3.7

STOCK Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

STOCK Cdkn1btm1Mlf (Unspecified organ) tumor (Unspecified organ)

17

STOCK Cdkn1btm1Mlf Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

STOCK Cdkn1btm1Mlf/+ Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

C57BL/6-Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

C57BL/6-Cdkn1btm1Mlf (Unspecified organ) tumor (Unspecified organ)

83

C57BL/6-Cdkn1btm1Mlf Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

C57BL/6-Cdkn1btm1Mlf/+ Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

[not specified]-Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

[not specified]-Cdkn1btm1Mlf (Unspecified organ) tumor (Unspecified organ)

43

[not specified]-Cdkn1btm1Mlf Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

[not specified]-Cdkn1btm1Mlf/+ Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

NIH.129S6-Cdkn1atm1Led (Unspecified organ) tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
(Unspecified organ)

100

NIH.129S6-Cdkn1atm1Led/+ (Unspecified organ) tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
(Unspecified organ)

100

NIH (Unspecified organ) tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
(Unspecified organ)

100