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Investigation of the dynamics and function of nuclear actin in response to different mechanical signals and composition of the extracellular matrix

Grant number: 17/18067-5
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): February 01, 2018
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Alexandre Bruni Cardoso
Grantee:Pedro de Freitas Ribeiro
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant: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, AP.JP

Abstract

Actin, a cytoskeleton protein, is involved in many cellular processes and can also be found inside the nucleus. Actin can assume the globular monomeric form (G-actin) or the filamentous form (F-actin) through polymerization, and the different forms of actin can also have different roles. In the nucleus, the roles played by the different forms of actin are not well understood and the regulation of actin monomer-filament dynamics in this compartment is also poorly known. The formation of actin filaments in the nucleus has already been described under specific conditions and may be regulated by mechanotransduction pathways. Mechanic cues such as the stiffness of the cell culture substrate and the cell geometry can influence nuclear processes and combined with the Extracellular Matrix (ECM) composition can influence cell behavior. The transcriptional factor SRF (Serum Responsive Factor), coupled with its coactivator MAL (Megakaryocytic acute leukemia protein), and the coactivator of transcription YAP (Yes Associated Protein) are capable of relaying external physical cues changing the gene expression. Nevertheless, the mechanisms used by these molecules to respond to mechanical stimuli require further investigation. Much evidence has shown that the actin cytoskeleton state is an important intermediate of physical signals. However, the direct or indirect connection between nuclear and cytosolic actin are still elusive. We propose to investigate the nuclear actin dynamics in different mechanical contexts varying the substrate stiffness using tunable hydrogels in combination with different ECM proteins. We seek at understanding the relevance and the function of the nuclear actin status in the activity of SRF and YAP. We will also investigate the role of the the LINC complex (linker of nucleoskeleton and cytoskeleton), that connects the nucleus to the cytoskeleton, in regulating nuclear actin status in the context of modulation of the substrate rigidity and composition by silencing of the SUN-1/2, essential proteins of the LINC complex. Nuclear actin probes that allows visualization of filaments will be used to monitor the dynamics of the actin forms in the nucleus. Two actin mutants directed to the nucleus, one that is incapable of polymerizing and another that generates stable filaments, will be used to modulate the actin state and to evaluate the effects of monomeric and filamentous forms on the activity of SRF and YAP. With the conclusion of this project we hope to establish if the ECM stiffness modulates the nuclear actin polymerization dynamics and to determinate if actin in the nucleus crosstalks with the classic mechanotransduction pathways. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ZEN PETISCO FIORE, ANA PAULA; RIBEIRO, PEDRO DE FREITAS; BRUNI-CARDOSO, ALEXANDRE. Sleeping Beauty and the Microenvironment Enchantment: Microenvironmental Regulation of the Proliferation-Quiescence Decision in Normal Tissues and in Cancer Development. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 6, . (17/18067-5, 14/25832-1, 14/10492-0, 17/18641-3)
ZEN PETISCO FIORE, ANA PAULA; RODRIGUES, ANA MARIA; RIBEIRO-FILHO, HELDER VERAS; MANUCCI, ANTONIO CARLOS; DE FREITAS RIBEIRO, PEDRO; SILVA BOTELHO, MAYARA CAROLINNE; VOGEL, CHRISTINE; LOPES-DE-OLIVEIRA, PAULO SERGIO; PAGANO, MICHELE; BRUNI-CARDOSO, ALEXANDRE. Extracellular matrix stiffness regulates degradation of MST2 via SCF beta TrCP. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1866, n. 12, p. 11-pg., . (17/25437-3, 17/18641-3, 18/00629-0, 14/25832-1, 14/10492-0, 17/18067-5, 19/26767-2)

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