RESUMO
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.
Assuntos
Glândulas Mamárias Animais/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/citologia , Feminino , Fase G1/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactação , Glândulas Mamárias Animais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas dos Microfilamentos , Fosforilação , Gravidez , Prenhez/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Células Tumorais CultivadasRESUMO
The erbB2 receptor tyrosine kinase and the CD44 transmembrane glycoprotein interact with one another in numerous cell types. This interaction helps to maintain erbB2 activity that contributes to tumor progression. We investigated whether CD44 and erbB2 similarly interact in endometrial carcinomas in vitro and in situ. In contrast to other carcinomas, CD44 did not colocalize with erbB2 in any of the 51 cases of endometrial cancer analyzed. CD44 also did not coimmunoprecipitate or colocalize with erbB2 in two endometrial carcinoma cell lines. We propose that the lack of CD44-erbB2 interactions may reduce the contribution of erbB2 to endometrial carcinoma progression.
