Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation.
4.1B is a member of the protein 4.1 superfamily of proteins that link transmembrane proteins to the actin cytoskeleton. The 4.1B gene localizes to chromosome 18p11.3, which undergoes loss of heterozygosity in mammary tumors. Here, we examine the expression of 4.1B in murine mammary epithelium and find that 4.1B is dramatically upregulated in mammary epithelial cells during pregnancy when there is extensive cell proliferation. In contrast, 4.1B is not expressed in virgin, lactating, or involuting mammary epithelium. To examine the consequence of 4.1B loss on mammary epithelial cell proliferation, we analysed mammary glands in 4.1B-null mice. 4.1B loss results in a significant increase in mammary epithelial cell proliferation during pregnancy, but has no effect on mammary epithelial cell proliferation, in virgin or involuting mice. Furthermore, we show that 4.1B inhibits the proliferation of mammary epithelial cell lines by inducing a G1 cell cycle arrest, characterized by decreased cyclin A expression and reduced Rb phosphorylation, and accompanied by reduced erbB2 phosphorylation. This cell cycle arrest does not involve alterations in the activities of MAPK, JNK, or Akt. Collectively, our findings demonstrate that 4.1B regulates mammary epithelial cell proliferation during pregnancy and suggest that its loss may influence mammary carcinoma pathogenesis in multiparous women.
Kuns
Robin
R
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA.
Kissil
Joseph L
JL
Newsham
Irene F
IF
Jacks
Tyler
T
Gutmann
David H
DH
Sherman
Larry S
LS
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D016193:G1 Phase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins; D010766:Phosphorylation; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C086680:ETV5 protein, human; C488402:Epb41l3 protein, mouse; C513242:Etv5 protein, mouse