CDP/Cutl1 controls differentiation-specific MMTV and cellular gene expression in the mammary gland

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Maitra, Urmila

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Mouse mammary tumor virus (MMTV) is a betaretrovirus that causes breast cancer in mice. Completion of the MMTV life cycle is linked to the differentiation status of the mammary gland. Virus expression is low during early stages of mammary development, but high levels of MMTV transcription occur during lactation to ensure optimal viral transmission through maternal milk to the offspring. Negative regulation has been shown to play a significant role in mediating tissue-specific MMTV expression. The cellular factor, CCAAT displacement protein (CDP), is a transcriptional repressor of MMTV. Virgin mammary glands have high levels of full-length CDP that binds to negative regulatory elements (NRE) to repress MMTV transcription. During late pregnancy, CDP DNA-binding activity declines concomitant with an increase in viral transcripts. This study demonstrated that reduction of full-length CDP levels in two independent strains of CDP knockout mice increased endogenous MMTV and other mammary-specific cellular genes in undifferentiated mammary glands, suggesting a critical role for CDP in the MMTV life cycle. Interestingly, CDP was developmentally regulated during mammary differentiation. During late pregnancy, the loss of full-length CDP coincided with the appearance of a novel, C-terminally truncated isoform of 150 kDa (CDP150). CDP is proteolytically processed within the homeodomain by a cysteine protease to generate a dominantnegative CDP150 protein that interferes with the DNA-binding and repressor activities of CDP. Furthermore, the loss of DNA-binding activity correlates with increased expression of MMTV and other mammary-specific genes, including β-casein, whey acidic protein and α-lactalbumin, indicating that CDP150 is a developmentally controlled, naturally occurring dominant-negative protein. Studies with mouse embryo fibroblasts lacking endogenous nuclear CDP confirmed that CDP150 lacks transcriptional repressor or activator function for the MMTV LTR and β-casein. Therefore, MMTV has adopted a normal cellular process to control viral expression during mammary differentiation. This study reveals a novel posttranslational cleavage event that controls CDP activity and gene expression during normal development of the mammary gland.