4.6 Article

Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity

Journal

FRONTIERS IN MOLECULAR BIOSCIENCES
Volume 9, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2022.992313

Keywords

ALMS1; alstrom syndrome; ciliopathies; primary cilia; TGF-beta; epithelial-mesenchymal transition (EMT); cell cycle arrest; apoptosis

Funding

  1. Instituto de Salud Carlos III
  2. Xunta de Galicia [PI15/00049, PI19/00332]
  3. Consolidacion e estructuracion de unidades de investigacion competitivas e outras accions de fomento (Xunta de Galicia) [ED431G-2019/06]
  4. Spanish Ministry of Education, Culture and Sports [ED431C-2018/54]
  5. [FPU17/01567]

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The research demonstrates that the ALMS1 gene plays a role in controlling the cell cycle and apoptosis processes. Depletion of ALMS1 affects the signal transduction through the TGF-beta pathway and other processes like cell migration and adhesion capacity.
Background: ALMS1 is a ubiquitous gene associated with Alstrom syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis in the lungs, kidneys and liver. TGF-beta is one of the main pathways implicated in fibrosis, controlling the cell cycle, apoptosis, cell migration, cell adhesion and epithelial-mesenchymal transition (EMT). Nevertheless, the role of ALMS1 gene in fibrosis generation and other implicated processes such as cell migration or cell adhesion via the TGF- beta pathway has not been elucidated yet. Methods: Initially, we evaluated how depletion of ALMS1 affects different processes like apoptosis, cell cycle and mitochondrial activity in HeLa cells. Then, we performed proteomic profiling with TGF-beta stimuli in HeLa ALMS1 -/-cells and validated the results by examining different EMT biomarkers using qPCR. The expression of these EMT biomarkers were also studied in hTERT-BJ-5ta ALMS1 -/-. Finally, we evaluated the SMAD3 and SMAD2 phosphorylation and cell migration capacity in both models. Results: Depletion of ALMS1 generated apoptosis resistance to thapsigargin (THAP) and C2-Ceramide (C2-C), and G2/M cell cycle arrest in HeLa cells. For mitochondrial activity, results did not show significant differences between ALMS1 +/+ and ALMS1-/-. Proteomic results showed inhibition of downstream pathways regulated by TGF-beta. The protein-coding genes (PCG) were associated with processes like focal adhesion or cell-substrate adherens junction in HeLa. SNAI1 showed an opposite pattern to what would be expected when activating the EMT in HeLa and BJ-5ta. Finally, in BJ-5ta model a reduced activation of SMAD3 but not SMAD2 were also observed. In HeLa model no alterations in the canonical TGF-beta pathway were observed but both cell lines showed a reduction in migration capacity. Conclusion: ALMS1 has a role in controlling the cell cycle and the apoptosis processes. Moreover, the depletion of ALMS1 affects the signal transduction through the TGF-beta and other processes like the cell migration and adhesion capacity.

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