DOI: 10.1101/gad.11.6.714. Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.

Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.

10.1101/gad.11.6.714

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

Abstract

MDM2 is a cellular protein that binds to and inactivates the p53 tumor suppressor protein. Although mdm2 has been shown to function as an oncogene in vitro, all studies to date have assessed MDM2 activities in the presence of p53, implicating p53 inactivation in MDM2-directed transformation. To determine the role of MDM2 in the cell cycle and in tumorigenesis and whether or not this role is dependent on p53, an MDM2 minigene was expressed during gestation and lactation in the mammary gland of both wild-type p53 (p53+/+) and p53 knockout (p53-/-) mice using the bovine beta-lactoglobulin promoter. In six different transgenic mouse lines, deregulated expression of MDM2 inhibited normal development and morphogenesis of the mammary gland, and caused cellular hypertrophy and nuclear abnormalities. These abnormalities included both multinucleated cells and enlarged cells with giant nuclei. Although there were fewer epithelial cells present in the transgenic mammary gland, no apoptosis was observed. Instead, BrdU incorporation and PCNA staining showed that 12%-27% of the transgenic mammary epithelial cells were in S phase at a time when normal cells were terminally differentiated. Analysis of DNA content showed that 30%-45% of the cells were polyploid, with DNA contents up to 16N, indicating that overexpression of MDM2 caused mammary epithelial cells to undergo multiple rounds of S phase without cell division. This phenotype was similar in the p53+/+ and p53-/- background, demonstrating a role for MDM2 in the regulation of DNA synthesis that is independent of the ability of MDM2 to inhibit p53 activity. Additionally, multiple lines of BLGMDM2 transgenic mice developed mammary tumors, confirming that overproduction of MDM2 contributes to tumorigenesis in epithelial cells in vivo.

Bibliography

Lundgren, K., Montes de Oca Luna, R., McNeill, Y. B., Emerick, E. P., Spencer, B., Barfield, C. R., Lozano, G., Rosenberg, M. P., & Finlay, C. A. (1997). Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes & Development, 11(6), 714â725.

Authors 9

K Lundgren (first)
R Montes de Oca Luna (additional)
Y B McNeill (additional)
E P Emerick (additional)
B Spencer (additional)
C R Barfield (additional)
G Lozano (additional)
M P Rosenberg (additional)
C A Finlay (additional)

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Dates

Type	When
Created	18 years, 2 months ago (June 5, 2007, 5:15 p.m.)
Deposited	3 years, 9 months ago (Nov. 14, 2021, 9:58 p.m.)
Indexed	1 month ago (July 23, 2025, 8:26 a.m.)
Issued	28 years, 5 months ago (March 15, 1997)
Published	28 years, 5 months ago (March 15, 1997)
Published Online	28 years, 5 months ago (March 15, 1997)
Published Print	28 years, 5 months ago (March 15, 1997)

Funders 0

None

BibTeX

@article{Lundgren_1997, title={Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.}, volume={11}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.11.6.714}, DOI={10.1101/gad.11.6.714}, number={6}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Lundgren, K and Montes de Oca Luna, R and McNeill, Y B and Emerick, E P and Spencer, B and Barfield, C R and Lozano, G and Rosenberg, M P and Finlay, C A}, year={1997}, month=mar, pages={714–725} }

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