Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6

Author(s)

Fiore, Ana Paula Zen Petisco ; Spencer, Virginia A. ; Mori, Hidetoshi ; Carvalho, Hernandes F. ; Bissell, Mina J. ; Bruni-Cardoso, Alexandre

• Document type: Journal article
• Source: CELL REPORTS; v. 19, n. 10, p. 2102-2115, JUN 6 2017.
• Web of Science Citations: 14

Abstract

Nuclear actin (N-actin) is known to participate in the regulation of gene expression. We showed previously that N-actin levels mediate the growth and quiescence of mouse epithelial cells in response to laminin-111 (LN1), a component of the mammary basement membrane (BM). We know that BM is defective in malignant cells, and we show here that it is the LN1/N-actin pathway that is aberrant in human breast cancer cells, leading to continuous growth. Photobleaching assays revealed that N-actin exit in nonmalignant cells begins as early as 30 min after LN1 treatment. LN1 attenuates the PI3K pathway leading to upregulation of exportin-6 (XPO6) activity and shuttles actin out of the nucleus. Silencing XPO6 prevents quiescence. Malignant cells are impervious to LN1 signaling. These results shed light on the crucial role of LN1 in quiescence and differentiation and how defects in the LN1/ PI3K/XPO6/N-actin axis explain the loss of tissue homeostasis and growth control that contributes to malignant progression. (AU)

• FAPESP's process: 14/25832-1 - Hippo-YAP pathway as a mediator of extracellular matrix signals in non-malignant and malignant epithelial cells of the mammary gland
• Grantee: Ana Paula Zen Petisco Fiore
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/10492-0 - Hippo-YAP as a converging pathway for biochemical and mechanical signals from the extracellular matrix during mammary gland morphogenesis and breast cancer progression
• Grantee: Alexandre Bruni Cardoso
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 14/50938-8 - INCT 2014: in Photonics Applied to Cell Biology
• Grantee: Hernandes Faustino de Carvalho
• Support Opportunities: Research Projects - Thematic Grants