A HIF-1 target, ATIA, protects cells from apoptosis by modulating the mitochondrial thioredoxin, TRX2

Swati Choksi1, Yong Lin, Yelena Pobezinskaya

  • 1Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.

Molecular Cell
|June 11, 2011
PubMed

Insights

A newly identified protein, Vasn/ATIA, protects cells from apoptosis by regulating mitochondrial reactive oxygen species (ROS). This protein is crucial in glioblastoma, suggesting it as a potential diagnostic and therapeutic target.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of apoptosis
  • Cancer research

Background:

  • Apoptosis regulation is vital for tissue homeostasis and cancer prevention.
  • Reactive oxygen species (ROS) play a significant role in apoptosis.
  • Hypoxia and TNFα are key inducers of apoptosis.

Purpose of the Study:

  • To identify and characterize novel regulators of apoptosis.
  • To investigate the role of Vasn/ATIA in cellular apoptosis.
  • To explore ATIA's potential as a diagnostic and therapeutic target in glioblastoma.

Main Methods:

  • Generation and analysis of ATIA knockout mice.
  • Investigation of mitochondrial antioxidant function and ROS generation.
  • Analysis of ATIA expression in human glioblastoma samples.
  • Assessment of ATIA knockdown effects on glioblastoma cell apoptosis.

Main Results:

  • Vasn/ATIA was identified as a HIF-1 target that protects against TNFα- and hypoxia-induced apoptosis.
  • ATIA regulates mitochondrial thioredoxin-2 function and ROS levels.
  • ATIA is highly expressed in human glioblastoma.
  • ATIA knockdown sensitizes glioblastoma cells to hypoxia-induced apoptosis.

Conclusions:

  • ATIA is a HIF-1 target involved in regulating mitochondrial redox pathways.
  • ATIA plays a protective role against apoptosis.
  • ATIA represents a potential diagnostic marker and therapeutic target for glioblastoma.

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
Cellular Injury V: Apoptosis and Autophagy01:22

Cellular Injury V: Apoptosis and Autophagy

Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.