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Vol. 15, Issue 5, 2302-2311, May 2004

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p19^ARF Determines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Submitted November 4, 2003; Revised January 30, 2004; Accepted February 27, 2004
Monitoring Editor: Keith Yamamoto

This study demonstrated, for the first time, the following events related to p19^ARF involvement in mammary gland development: 1) Progesterone appears to regulate p19^ARF in normal mammary gland during pregnancy. 2) p19^ARF expression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19^ARF protein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19^ARF in mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21^Cip1 and decrease in apoptosis, and 2) p19^ARF null cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21^Cip1 compared with WT cells. Although, p19^ARF is dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19^ARF null mice, the upregulation of p19^ARF by progesterone in the WT cells and the weakness of p21^Cip1 in mammary epithelial cells lacking p19^ARF strongly suggest that the functional role(s) of p19^ARF 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.

^* Corresponding author. E-mail address: tsaid{at}bcm.tmc.edu.

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