miR-128 Is Implicated in Stress Responses by Targeting MAFG in Skeletal Muscle Cells

Rocco Caggiano1, Fabio Cattaneo1,2, Ornella Moltedo3

  • 1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Napoli, Italy.

Insights

MicroRNA-128 directly targets MAFG, a transcriptional regulator involved in stress response pathways. This interaction impairs antioxidant and xenobiotic defenses mediated by Nrf2, highlighting a novel regulatory mechanism in cellular stress adaptation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cellular Stress Response

Background:

  • Small MAF (sMAF) proteins, including MAFG, are bZIP transcriptional regulators that form dimers to control gene expression.
  • MAFG, as a partner of Nrf2, modulates antioxidant and xenobiotic pathways via the ARE.
  • The role of microRNAs (miRs) in regulating stress response pathways involving MAFG and Nrf2 is not well understood.

Purpose of the Study:

  • To investigate the impact of miR-128 on gene expression related to cellular stress response.
  • To determine if MAFG is a direct target of miR-128.
  • To elucidate the functional consequences of miR-128 regulation on MAFG-Nrf2 mediated pathways.

Main Methods:

  • Bioinformatic prediction of miR-128 binding sites in MAFG 3'UTR.
  • Functional analysis including ectopic miR-128 expression.
  • Assessment of MAFG-dependent gene expression and ARE-mediated Nrf2 activity.
  • Analysis of gene expression (HMOX-1, x-CT) under hypoxia.

Main Results:

  • miR-128 directly binds to the 3'UTR of MAFG mRNA.
  • Ectopic miR-128 expression reduces MAFG-dependent gene expression and impairs Nrf2/ARE activity.
  • miR-128 negatively affects redox-dependent pathways during oxidative stress.
  • Hypoxia induces MAFG, which correlates with reduced miR-128, leading to increased HMOX-1 and x-CT expression.

Conclusions:

  • MAFG is identified as a novel direct target of miR-128.
  • miR-128 negatively regulates MAFG expression and its role in ARE-mediated stress response.
  • This study reveals a new layer of microRNA-mediated control over cellular surveillance to stress.

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.6K
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.9K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.7K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.9K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.7K