p19ARFDetermines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development

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Abstract
This study demonstrated, for the first time, the following events related to p19ARF involvement in mammary gland development: 1) Progesterone appears to regulate p19ARF in normal mammary gland during pregnancy. 2) p19ARF expression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19ARF protein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19ARF in mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21Cip1 and decrease in apoptosis, and 2) p19ARF null cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21Cip1 compared with WT cells. Although, p19ARF is dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19ARF null mice, the upregulation of p19ARF by progesterone in the WT cells and the weakness of p21Cip1 in mammary epithelial cells lacking p19ARF strongly suggest that the functional role(s) of p19ARF in mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.