Cripto-1 inhibits β-casein expression in mammary epithelial cells through a p21(ras)-and phosphatidylinositol 3'-kinase-dependent pathway

Marta L. De Santis, Subha Kannan, Gilbert H. Smith, Masaharu Seno, Caterina Bianco, Nancy Kim, Isabel Martinez-Lacaci, Brenda Wallace-Jones, David S. Salomon

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Abstract

Cripto-1 (CR-1) is a recently discovered protein of the epidermal growth factor family that does not directly activate any of the known erbB type 1 tyrosine kinase receptors. Also, CR-1 stimulates the growth of HC-11 mouse mammary epithelial cells. We found that prior treatment of HC-11 cells with exogenous CR-1 induced a competency response to the lactogenic hormones dexamethasone, insulin, and prolactin (DIP) with respect to the induction of the milk protein β-casein. In contrast, simultaneous treatment of mouse HC- 11 cells with CR-1 in the presence of DIP inhibited β-casein expression. The inhibitory effects of CR-1 on β-casein expression in response to DIP were not unique to this mouse mammary epithelial cell line, because β-casein and whey acidic protein expression in primary mouse mammary explant cultures established from midpregnant mice were also differentially inhibited by several epidermal growth factor-related peptides including CR-1. The mitogenic and differentiation effects of CR-1 are mediated by the binding of CR-1 to a cell surface receptor that is known to activate the ras/raf/mitogen-activated protein kinase (MAPK)/MAPK kinase pathway. The inhibitory response of CR-1 in HC-11 cells on β-casein expression after treatment with DIP can be attenuated by B581, a peptidomimetic farnesyltransferase inhibitor that blocks p21(ras) farnesylation and activation, and by the phosphatidylinositol 3'-kinase (PI3k) inhibitor LY 294002 but not by PD 98059, a MAPK kinase inhibitor that blocks MAPK activation. These data suggest that the ability of CR-1 to block lactogenic hormone-induced expression of β-casein is mediated through a p21(ras)- dependent, PI3k-mediated pathway. This is further substantiated by the observation that CR-1 is able to stimulate the tyrosine phosphorylation of the p85 PI3k regulatory subunit and to increase the activity of PI3k in HC- 11 cells.

Original languageEnglish
Pages (from-to)1257-1266
Number of pages10
JournalCell Growth and Differentiation
Volume8
Issue number12
Publication statusPublished - Dec 1997

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    De Santis, M. L., Kannan, S., Smith, G. H., Seno, M., Bianco, C., Kim, N., Martinez-Lacaci, I., Wallace-Jones, B., & Salomon, D. S. (1997). Cripto-1 inhibits β-casein expression in mammary epithelial cells through a p21(ras)-and phosphatidylinositol 3'-kinase-dependent pathway. Cell Growth and Differentiation, 8(12), 1257-1266.