Subunit S5a of the 26S proteasome is regulated by antiapoptotic signals

Yael Gus1, Rotem Karni, Alexander Levitzki

  • 1The Hebrew University, Department of Biological Chemistry, Silberman Institute, Givat Ram, Jerusalem 91904, Israel.

The FEBS Journal
|April 27, 2007
PubMed

Insights

The 26S proteasome subunit S5a acts as an antiapoptotic gene regulated by c-Src. Upregulation of S5a by antiapoptotic signals promotes cell survival.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The oncoprotein c-Src plays a role in cell survival and apoptosis.
  • Identifying novel antiapoptotic genes regulated by c-Src is crucial for understanding cancer progression.

Purpose of the Study:

  • To identify novel antiapoptotic genes regulated by c-Src.
  • To investigate the role of the 26S proteasome subunit S5a in apoptosis.

Main Methods:

  • Functional genetic screen to identify antiapoptotic genes.
  • Quantitative real-time PCR and Western blotting to assess S5a mRNA and protein levels.
  • Reporter assays and electrophoretic mobility shift assays (EMSA) to analyze S5a promoter activity and transcription factor binding.

Main Results:

  • The 26S proteasome subunit S5a was identified as a novel antiapoptotic gene.
  • S5a expression is downregulated by c-Src inhibition and upregulated in cells with high c-Src activity.
  • S5a transcription is regulated by the Tcf/Lef-1 transcription factor and influenced by signaling pathways including PI3K.

Conclusions:

  • S5a is transcriptionally regulated during apoptosis.
  • Upregulation of S5a by antiapoptotic signals contributes to cell survival.
  • S5a represents a potential therapeutic target in cancers driven by c-Src.

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 Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...