Reference SummaryMcPherson JP, Genes Dev 2004 May 15;18(10):1144-53

Title

Collaboration of Brca1 and Chk2 in tumorigenesis.

Authors

McPherson JP; Lemmers B; Hirao A; Hakem A; Abraham J; Migon E; Matysiak-Zablocki E; Tamblyn L; Sanchez-Sweatman O; Khokha R; Squire J; Hande MP; Mak TW; Hakem R

Journal

Genes Dev

Volume

18

Issue

10

Year

2004

Pages

1144-53

Abstract

Disruption of Brca1 results in cellular demise or tumorigenesis depending on cellular context. Inactivation of p53 contributes to Brca1-associated tumor susceptibility. However the activation of p53-dependent checkpoint/apoptotic signaling in the absence of Brca1 is poorly understood. Here, we show that Chk2 inactivation is partially equivalent to p53 inactivation, in that Chk2 deficiency facilitates the development, survival, and proliferation of Brca1-deficient T cells at the expense of genomic integrity. Brca1 deficiency was found to result in Chk2 phosphorylation and the Chk2-dependent accumulation and activation of p53. Furthermore, inactivation of Chk2 and Brca1 was cooperative in breast cancer. Our findings identify a critical role for Chk2 as a component of the DNA damage-signaling pathway activated in response to Brca1 deficiency.

Links

J:90512 – Mouse Genome Informatics
15131084 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Intestine - Large Intestine - Colon carcinoma Intestine - Large Intestine - Colon

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Leukocyte - Lymphocyte - B-lymphocyte lymphoma Leukocyte - Lymphocyte - B-lymphocyte

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Leukocyte - Lymphocyte - T-lymphocyte lymphoma Leukocyte - Lymphocyte - T-lymphocyte

observed

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm Trp53tm1Brd Leukocyte - Lymphocyte lymphoma Thymus

100

B6;129-Brca1tm2Mak/+ Tg(Lck-cre)548Jxm Trp53tm1Brd Leukocyte - Lymphocyte lymphoma Thymus

observed

B6;129-Trp53tm1Brd Leukocyte - Lymphocyte lymphoma Thymus

observed

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm Leukocyte - Lymphocyte lymphoma Lymphoid tissue

observed

B6;129-Chek2tm1Mak Leukocyte lymphoma Thymus

0 - observed

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Lck-cre)548Jxm Leukocyte lymphoma Thymus

31.82

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm Leukocyte lymphoma Thymus

0 - 12.12

B6;129-Trp53tm1Brd Leukocyte lymphoma Leukocyte

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Leukocyte lymphoma Leukocyte

observed

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm Trp53tm1Brd Leukocyte lymphoma Thymus

100

B6;129-Brca1tm2Mak/+ Tg(Lck-cre)548Jxm Trp53tm1Brd Leukocyte lymphoma Thymus

95.24

B6;129-Trp53tm1Brd Leukocyte lymphoma Thymus

100

B6;129-Brca1tm2Mak/+ Chek2tm1Mak Tg(Lck-cre)548Jxm Leukocyte lymphoma Thymus

0

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm Leukocyte lymphoma Stomach

observed

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm Leukocyte lymphoma Spleen

observed

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland adenocarcinoma - acinar Mammary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Mammary gland adenocarcinoma - acinar Mammary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd/+ Mammary gland adenocarcinoma - acinar Mammary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd/+ Mammary gland adenocarcinoma - well-differentiated Mammary gland

observed

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland carcinoma Mammary gland

observed - 50

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd/+ Mammary gland carcinoma Mammary gland

observed - 80

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland carcinoma - acinar Mammary gland

observed

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland carcinoma - adenosquamous Mammary gland

observed

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland neoplasia Mammary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Mammary gland tumor Mammary gland

11.76 - 17

B6;129-Chek2tm1Mak Mammary gland tumor Mammary gland

0 - observed

B6;129-Brca1tm2Mak Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland tumor Mammary gland

observed - 50

B6;129-Brca1tm2Mak/+ Chek2tm1Mak Tg(Wap-cre)11738Mam Mammary gland tumor Mammary gland

0 - observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd/+ Mammary gland tumor Mammary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Salivary gland adenocarcinoma Salivary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Salivary gland carcinoma Salivary gland

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Skin carcinoma Skin

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd Subcutis carcinoma Subcutis

observed

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd (Unspecified organ) carcinoma (Unspecified organ)

observed

B6;129-Brca1tm2Mak/+ Tg(Lck-cre)548Jxm Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

observed

B6;129-Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

observed

B6;129-Brca1tm2Mak Tg(Lck-cre)548Jxm (Unspecified organ) tumor (Unspecified organ)

12.12

B6;129-Chek2tm1Mak (Unspecified organ) tumor (Unspecified organ)

0

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

observed - 100

B6;129-Trp53tm1Brd (Unspecified organ) tumor (Unspecified organ)

100

B6;129-Brca1tm2Mak Tg(Wap-cre)11738Mam (Unspecified organ) tumor (Unspecified organ)

55