Biology subjects

Fidalgo da Silva, E.

Publications and source records attributed to Fidalgo da Silva, E..

3 recordsLinked to original sources

bioRxiv2026

Effects of ERK1/2 Signaling on Cell Cycle Regulation by the Tuberin-Cyclin B1 Complex

How cells balance growth (cell size) and division (cell number) requires a complex interplay between response to external signals including growth factors, nutrient availability and metabolic cues, along with regulation of the cell cycle. The protein Tuberin (gene TSC2) is a critical regulator of these decisions. In a complex with the protein Hamartin, Tuberin functions as a negative regulator of the Target of Rapamycin (mTOR) pathway, preventing excessive growth under unfavorable conditions. However, how this growth pathway connects to decisions to progress through the G2 phase of the cell cycle and permit cell division is still unclear. In this study, we show that post-translational modification of Tuberin by the Extracellular Signal-Regulated Kinase (ERK) pathway abrogates binding between Tuberin and the mitotic cyclin, Cyclin B1. This causes an increase in mitotic cells, due to an unregulated G2/M transition, increasing the proliferation rate. Our work shows a novel role of Tuberin in cell cycle regulation by growth and mitogenic factors independent of mTOR regulation.

cell biology↗

bioRxiv2021

Dissecting the Roles of the Tuberin Protein in the Subcellular Localization of the G2/M Cyclin, Cyclin B1

Tuberin is a major component of the protein regulatory complex known as the Tuberous Sclerosis Complex and plays a crucial role in cell cycle progression and protein synthesis. Mutations in the Tuberin gene, TSC2, lead to the formation of benign tumors in many organ systems and causes the Tuberous Sclerosis Complex disorder. Genotypes ranging from point mutations to large deletions in the TSC2 gene have been clinically characterized with a wide range of phenotypes from skin tumors to large brain tumors. Our current work investigates the molecular mechanisms behind Tuberin and its ability to regulate the cell cycle through its binding to the G2/M cyclin, Cyclin B1. After creating an early stop codon in a critical region of the Tuberin, our results show the in vitro phenotype that occurs from a truncated Tuberin protein. Herein we demonstrate that this clinically relevant truncated form of Tuberin promotes an increased nuclear accumulation of Cyclin B1 and a subsequent increase in cell proliferation supporting the phenotypic data seen in the clinic with Tuberous Sclerosis Complex patients showing deletions within the TSC2 gene. This data provides an insight into some of the functional and molecular consequences of truncated proteins that are seen in clinical patients.

cell biology↗

bioRxiv2021

Tuberin levels during cellular differentiation in brain development

Tuberin is a member of a large protein complex, Tuberous Sclerosis Complex, and acts as a sensor for nutrient status regulating protein synthesis and cell cycle progression. Mutations in the Tuberin gene, TSC2, lead to the formation of tumors and developmental defects in many organ systems, including the central nervous system. Tuberin is expressed in the brain throughout development and levels of Tuberin have been found to decrease during neuronal differentiation in cell lines in vitro. Our current work investigates the levels of Tuberin at two stages of embryonic development in vivo, and we study the mRNA and protein levels during a time course using immortalized cell lines in vitro. Our results show that Tuberin levels remain stable in the olfactory bulb but decrease in the Purkinje cell layer during embryonic mouse brain development. We show here that Tuberin levels are higher when cells are cultured as neurospheres, and knockdown of Tuberin results in a reduction in the number of neurospheres. These data provide support for the hypothesis that Tuberin is an important regulator of stemness and the reduction of Tuberin levels might support functional differentiation in the central nervous system. Understanding how Tuberin expression is regulated throughout neural development is essential to fully comprehend the role of this protein in several developmental and neural pathologies. HIGHLIGHTSO_LITuberin protein levels are decreased in the Purkinje cell layer in later stages of embryonic development. C_LIO_LITuberin protein and mRNA levels decrease as cells undergo neuronal differentiation. C_LIO_LIDownregulation of Tuberin impairs neurosphere formation. C_LIO_LITuberin is implicated in the maintenance of stemness in the developing brain. C_LI

developmental biology↗