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

Yazinski, Stephanie A, Westcott, Peter MK, Ong, Kelly, Pinkas, Jan, Peters, Rachel M, Weiss, Robert S (December 2009) Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration. Proceedings of the National Academy of Sciences of the United States of America, 106 (50). pp. 21282-21287. ISSN 0027-8424

PDF Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue re.pdf - Published Version Available under License Creative Commons Attribution. Download (2MB)

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.

Item Type:	Paper
Subjects:	organism description > animal organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Westcott, Peter
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	15 December 2009
Date Deposited:	20 Dec 2023 19:50
Last Modified:	20 Dec 2023 19:50
PMCID:	PMC2795509
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41346

Actions (login required)

Administrator's edit/view item