G-protein signaling abnormalities mediated by CD95 in salivary epithelial cells

X B Liu1, R Masago, L Kong

  • 1Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, TX 78229-3900, USA.

Insights

Overexpressing Bcl-2 and Bcl-xL in salivary cells prevents apoptosis but leads to caspase activity and impaired function, potentially explaining Sjögren

Area of Science:

  • Cell Biology
  • Immunology
  • Oncology

Background:

  • Primary Sjögren's syndrome (SS) involves Fas-mediated apoptosis in salivary epithelial cells.
  • The roles of apoptosis-suppressing oncogenes Bcl-2 and Bcl-xL in salivary cells are poorly understood.
  • Understanding these oncogenes may offer strategies to prevent salivary gland destruction in SS.

Purpose of the Study:

  • To investigate the potential of Bcl-2 and Bcl-xL to prevent salivary gland destruction in SS.
  • To examine the effects of Bcl-2 and Bcl-xL overexpression on Fas-mediated apoptosis and cell function in salivary epithelial cells.

Main Methods:

  • HSY human salivary epithelial cells were stably transfected with Bcl-2 or Bcl-xL expression vectors.
  • Apoptosis was induced using anti-Fas antibody and quantified via flow cytometry.
  • Caspase activity, Ca2+ mobilization, and response to receptor agonists (carbachol, EGF) were measured.

Main Results:

  • Bcl-2 and Bcl-xL significantly inhibited Fas-mediated apoptosis in transfected cells.
  • Surprisingly, caspase activity remained despite apoptosis inhibition.
  • Fas activation in Bcl-2/Bcl-xL transfectants reduced cell responsiveness to agonists, an effect partially restored by caspase inhibition.

Conclusions:

  • Overexpression of Bcl-2 and Bcl-xL in salivary epithelial cells prevents Fas-mediated apoptosis but results in cells with active caspases.
  • These damaged cells exhibit impaired responsiveness to receptor agonists, potentially explaining severe dryness in SS patients.
  • This suggests a mechanism where inhibited apoptosis leads to dysfunctional cells, contributing to SS pathogenesis beyond cell death alone.

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...