p19ARF determines the balance between normal cell proliferation rate and apoptosis during mammary gland development.
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.
Yi
Yijun
Y
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Shepard
Anne
A
Kittrell
Frances
F
Mulac-Jericevic
Biserka
B
Medina
Daniel
D
Said
Thenaa K
TK
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism; D002455:Cell Division; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005260:Female; D015870:Gene Expression; D007774:Lactation / Q000502:physiology; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development* / Q000637:transplantation; D051379:Mice; D008817:Mice, Mutant Strains; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025803:Tumor Suppressor Protein p14ARF; D011374:Progesterone; D001973:Bromodeoxyuridine