Cell Growth & Differentiation, Vol 8, Issue 12 1257-1266, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Cripto-1 inhibits beta-casein expression in mammary epithelial cells through a p21ras-and phosphatidylinositol 3'-kinase-dependent pathway

ML De Santis, S Kannan, GH Smith, M Seno, C Bianco, N Kim, I Martinez-Lacaci, B Wallace-Jones and DS Salomon
Tumor Growth Factor Section, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.

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 beta-casein. In contrast, simultaneous treatment of mouse HC-11 cells with CR-1 in the presence of DIP inhibited beta-casein expression. The inhibitory effects of CR-1 on beta-casein expression in response to DIP were not unique to this mouse mammary epithelial cell line, because beta-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 beta-casein expression after treatment with DIP can be attenuated by B581, a peptidomimetic farnesyltransferase inhibitor that blocks p21ras 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 beta-casein is mediated through a p21ras-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.

This article has been cited by other articles:

				S. Shi, C. Ge, Y. Luo, X. Hou, R. S. Haltiwanger, and P. Stanley The Threonine That Carries Fucose, but Not Fucose, Is Required for Cripto to Facilitate Nodal Signaling J. Biol. Chem., July 13, 2007; 282(28): 20133 - 20141. [Abstract] [Full Text] [PDF]

				J. Chu, J. Ding, K. Jeays-Ward, S. M. Price, M. Placzek, and M. M. Shen Non-cell-autonomous role for Cripto in axial midline formation during vertebrate embryogenesis Development, December 15, 2005; 132(24): 5539 - 5551. [Abstract] [Full Text] [PDF]

				L. Strizzi, C. Bianco, A. Raafat, W. Abdallah, C. Chang, D. Raafat, M. Hirota, S. Hamada, Y. Sun, N. Normanno, et al. Netrin-1 regulates invasion and migration of mouse mammary epithelial cells overexpressing Cripto-1 in vitro and in vivo J. Cell Sci., October 15, 2005; 118(20): 4633 - 4643. [Abstract] [Full Text] [PDF]

				Y. Sun, L. Strizzi, A. Raafat, M. Hirota, C. Bianco, L. Feigenbaum, N. Kenney, C. Wechselberger, R. Callahan, and D. S. Salomon Overexpression of Human Cripto-1 in Transgenic Mice Delays Mammary Gland Development and Differentiation and Induces Mammary Tumorigenesis Am. J. Pathol., August 1, 2005; 167(2): 585 - 597. [Abstract] [Full Text] [PDF]

				P. C. Gray, C. A. Harrison, and W. Vale Cripto forms a complex with activin and type II activin receptors and can block activin signaling PNAS, April 29, 2003; 100(9): 5193 - 5198. [Abstract] [Full Text] [PDF]

				C. Bianco, L. Strizzi, A. Rehman, N. Normanno, C. Wechselberger, Y. Sun, N. Khan, M. Hirota, H. Adkins, K. Williams, et al. A Nodal- and ALK4-independent Signaling Pathway Activated by Cripto-1 through Glypican-1 and c-Src Cancer Res., March 15, 2003; 63(6): 1192 - 1197. [Abstract] [Full Text] [PDF]

				C. Bianco, H. B. Adkins, C. Wechselberger, M. Seno, N. Normanno, A. De Luca, Y. Sun, N. Khan, N. Kenney, A. Ebert, et al. Cripto-1 Activates Nodal- and ALK4-Dependent and -Independent Signaling Pathways in Mammary Epithelial Cells Mol. Cell. Biol., April 15, 2002; 22(8): 2586 - 2597. [Abstract] [Full Text] [PDF]

				L. Shan, S. A. Rouhani, H. A. J. Schut, and E. G. Snyderwine 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Modulates Lactogenic Hormone-mediated Differentiation and Gene Expression in HC11 Mouse Mammary Epithelial Cells Cell Growth Differ., December 1, 2001; 12(12): 649 - 656. [Abstract] [Full Text] [PDF]

				A. A. Adjei Blocking Oncogenic Ras Signaling for Cancer Therapy J Natl Cancer Inst, July 18, 2001; 93(14): 1062 - 1074. [Abstract] [Full Text] [PDF]

				E. K. Rowinsky, J. J. Windle, and D. D. Von Hoff Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development J. Clin. Oncol., November 1, 1999; 17(11): 3631 - 3652. [Abstract] [Full Text] [PDF]

				A. D. Ebert, C. Wechselberger, S. Frank, B. Wallace-Jones, M. Seno, I. Martinez-Lacaci, C. Bianco, M. De Santis, H. K. Weitzel, and D. S. Salomon Cripto-1 Induces Phosphatidylinositol 3'-Kinase-dependent Phosphorylation of AKT and Glycogen Synthase Kinase 3{beta} in Human Cervical Carcinoma Cells Cancer Res., September 1, 1999; 59(18): 4502 - 4505. [Abstract] [Full Text] [PDF]

				M. E. Benton, K.-S. Chen, J. D. Haag, C. A. Sattler, and M. N. Gould Precocious Differentiation of the Virgin Wistar-Kyoto Rat Mammary Gland Endocrinology, June 1, 1999; 140(6): 2659 - 2671. [Abstract] [Full Text]

				C. Bianco, S. Kannan, M. De Santis, M. Seno, C. K. Tang, I. Martinez-Lacaci, N. Kim, B. Wallace-Jones, M. E. Lippman, A. D. Ebert, et al. Cripto-1 Indirectly Stimulates the Tyrosine Phosphorylation of erb B-4 through a Novel Receptor J. Biol. Chem., March 26, 1999; 274(13): 8624 - 8629. [Abstract] [Full Text] [PDF]

				S. G. Schiffer, S. Foley, A. Kaffashan, X. Hronowski, A. E. Zichittella, C.-Y. Yeo, K. Miatkowski, H. B. Adkins, B. Damon, M. Whitman, et al. Fucosylation of Cripto Is Required for Its Ability to Facilitate Nodal Signaling J. Biol. Chem., October 5, 2001; 276(41): 37769 - 37778. [Abstract] [Full Text] [PDF]