CDP/Cutl1 controls differentiation-specific MMTV and cellular gene expression in the mammary gland
Year: 2006
Type: dissertation
Abstract: Mouse mammary tumor virus (MMTV) is a betaretrovirus that causes \nbreast cancer in mice. Completion of the MMTV life cycle is linked to the \ndifferentiation status of the mammary gland. Virus expression is low during early \nstages of mammary development, but high levels of MMTV transcription occur \nduring lactation to ensure optimal viral transmission through maternal milk to the \noffspring. Negative regulation has been shown to play a significant role in mediating \ntissue-specific MMTV expression. \nThe cellular factor, CCAAT displacement protein (CDP), is a transcriptional \nrepressor of MMTV. Virgin mammary glands have high levels of full-length CDP \nthat binds to negative regulatory elements (NRE) to repress MMTV transcription. \nDuring late pregnancy, CDP DNA-binding activity declines concomitant with an \nincrease in viral transcripts. This study demonstrated that reduction of full-length \nCDP levels in two independent strains of CDP knockout mice increased endogenous \nMMTV and other mammary-specific cellular genes in undifferentiated mammary \nglands, suggesting a critical role for CDP in the MMTV life cycle. Interestingly, \nCDP was developmentally regulated during mammary differentiation. During late \npregnancy, the loss of full-length CDP coincided with the appearance of a novel, \nC-terminally truncated isoform of 150 kDa (CDP150). CDP is proteolytically \nprocessed within the homeodomain by a cysteine protease to generate a dominantnegative \nCDP150 protein that interferes with the DNA-binding and repressor \nactivities of CDP. Furthermore, the loss of DNA-binding activity correlates with \nincreased expression of MMTV and other mammary-specific genes, including \nβ-casein, whey acidic protein and α-lactalbumin, indicating that CDP150 is a \ndevelopmentally controlled, naturally occurring dominant-negative protein. Studies \nwith mouse embryo fibroblasts lacking endogenous nuclear CDP confirmed that \nCDP150 lacks transcriptional repressor or activator function for the MMTV LTR \nand β-casein. Therefore, MMTV has adopted a normal cellular process to control \nviral expression during mammary differentiation. This study reveals a novel posttranslational \ncleavage event that controls CDP activity and gene expression during \nnormal development of the mammary gland.
Author: Urmila Maitra
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2120970759