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Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration.

ABSTRACT: In response to DNA damage, checkpoint proteins halt cell cycle progression and promote repair or apoptosis, thereby preventing mutation accumulation and suppressing tumor development. The DNA damage checkpoint protein Hus1 associates with Rad9 and Rad1 to form the 9-1-1 complex, which localizes to DNA lesions and promotes DNA damage signaling and repair. Because complete inactivation of mouse Hus1 results in embryonic lethality, we developed a system for regulated Hus1 inactivation in the mammary gland to examine roles for Hus1 in tissue homeostasis and tumor suppression. Hus1 inactivation in the mammary epithelium resulted in genome damage that induced apoptosis and led to depletion of Hus1-null cells from the mammary gland. Conditional Hus1 knockout females retained grossly normal mammary gland morphology, suggesting compensation by cells that failed to undergo Cre-mediated Hus1 deletion. p53-deficiency delayed the clearance of Hus1-null cells from conditional Hus1 knockout mice and caused the accumulation of damaged, dying cells in the mammary gland. Notably, compensatory responses were impaired following combined Hus1 and p53 loss, resulting in aberrant mammary gland morphology and lactation defects. Overall, these results establish a requirement for Hus1 in the survival and proliferation of mammary epithelium and identify a role for p53 in mammary gland tissue regeneration and homeostasis.

SUBMITTER: Yazinski SA

PROVIDER: S-EPMC2795509 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration.

Yazinski Stephanie A SA Westcott Peter M K PM Ong Kelly K Pinkas Jan J Peters Rachel M RM Weiss Robert S RS

Proceedings of the National Academy of Sciences of the United States of America 20091116 50

In response to DNA damage, checkpoint proteins halt cell cycle progression and promote repair or apoptosis, thereby preventing mutation accumulation and suppressing tumor development. The DNA damage checkpoint protein Hus1 associates with Rad9 and Rad1 to form the 9-1-1 complex, which localizes to DNA lesions and promotes DNA damage signaling and repair. Because complete inactivation of mouse Hus1 results in embryonic lethality, we developed a system for regulated Hus1 inactivation in the mammar ...[more]

PMID: 19918068

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Project description:Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy. Early menopause and sterility are unintended consequences of chemotherapy, and efforts to understand the oocyte apoptotic pathway may provide new targets for mitigating this outcome. Recently, the c-Abl kinase inhibitor imatinib mesylate (imatinib) has become the focus of research as a fertoprotective drug against cisplatin. However, the mechanism by which imatinib protects oocytes is not fully understood, and reports of the drug's efficacy have been contradictory. Using in vitro culture and subrenal grafting of mouse ovaries, we demonstrated that imatinib inhibits the cisplatin-induced apoptosis of oocytes within primordial follicles. We found that, before apoptosis, cisplatin induces c-Abl and TAp73 expression in the oocyte. Oocytes undergoing apoptosis showed downregulation of TAp63 and upregulation of Bax. While imatinib was unable to block cisplatin-induced DNA damage and damage response, such as the upregulation of p53, imatinib inhibited the cisplatin-induced nuclear accumulation of c-Abl/TAp73 and the subsequent downregulation of TAp63 and upregulation of Bax, thereby abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63, but not ?Np63, in oocytes inhibited apoptosis, as well as the accumulation of c-Abl and TAp73 caused by cisplatin. These data suggest that TAp63 is the master regulator of cisplatin-induced oocyte death. The expression kinetics of TAp63, c-Abl and TAp73 suggest that cisplatin activates TAp63-dependent expression of c-Abl and TAp73 and, in turn, the activation of TAp73 by c-Abl-induced BAX expression. Our findings indicate that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would otherwise activate TAp73-BAX-mediated apoptosis. Thus, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt cisplatin-induced oocyte death in early follicles and perhaps conserve the endocrine function of the ovary against chemotherapy.

Project description:Throughout life, the tight equilibrium between cell death and the prompt clearance of dead corpses is required to maintain a proper tissue homeostasis and prevent inflammation. Following lactation, mammary gland involution is triggered and results in the death of excessive epithelial cells that are rapidly cleared by phagocytes to ensure that the gland returns to its prepregnant state. Orthologs of Dock1 (dedicator of cytokinesis 1), Elmo and Rac1 (ras-related C3 botulinum toxin substrate 1) in Caenorhabditis elegans are part of a signaling module in phagocytes that is linking apoptotic cell recognition to cytoskeletal reorganization required for engulfment. In mammals, Elmo1 was shown to interact with the phosphatidylserine receptor Bai1 and relay signals to promote phagocytosis of apoptotic cells. Still, the role of the RacGEF Dock1 in the clearance of dying cells in mammals was never directly addressed. We generated two mouse models with conditional inactivation of Dock1 and Rac1 and revealed that the expression of these genes is not essential in the mammary gland during puberty, pregnancy and lactation. We induced mammary gland involution in these mice to investigate the role of Dock1/Rac1 signaling in the engulfment of cell corpses. Unpredictably, activation of Stat3 (signal transducer and activator of transcription 3), a key regulator of mammary gland involution, was impaired in the absence of Rac1 and Dock1 expression. Likewise, failure to activate properly Stat3 was coinciding with a significant delay in the initiation and progression of mammary gland involution in mutant animals. By using an in vitro phagocytosis assay, we observed that Dock1 and Rac1 are essential to mediate engulfment in epithelial phagocytes. In vivo, cell corpses accumulated at late time points of involution in Dock1 and Rac1 mutant mammary glands. Overall, our study demonstrated an unsuspected role for Dock1/Rac1 signaling in the initiation of mammary gland involution, and also suggested a role for this pathway in the clearance of dead cells by epithelial phagocytes.

Dataset Information

Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration.

Publications

Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration.

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