The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis

Pingbo Chen1, Beibei Wang1, Qingqing Mo1

  • 1Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.

Ebiomedicine
|October 23, 2019
PubMed
Abstract

Insights

The LIV-1-GRPEL1 axis controls cell death or survival during mitotic arrest. This axis regulates mitotic exit and apoptosis, offering new insights into cell fate mechanisms in cancer.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Cellular response to mitotic poisons is critical for cancer treatment.
  • Mechanisms determining cell death versus survival during anti-mitotic drug exposure are largely unknown.

Purpose of the Study:

  • To elucidate the roles of SLC39A6 (LIV-1) and GrpE-like 1 (GRPEL1) in regulating mitotic exit and apoptosis.
  • To investigate the LIV-1-GRPEL1 axis in the context of anti-mitotic drug response and cancer.

Main Methods:

  • In vitro and in vivo studies using flow cytometry, western blotting, xenografts, and time-lapse imaging.
  • Protein interaction and ubiquitination analyses (GST pull-down, immunoprecipitation, mass spectrometry).
  • Immunohistochemistry to assess LIV-1 expression in human cancers.

Main Results:

  • LIV-1 overexpression induced apoptosis; LIV-1 depletion promoted mitotic exit from arrest.
  • The LIV-1-GRPEL1 axis stabilizes GRPEL1 by preventing its ubiquitination.
  • This axis modulates mitotic arrest via PP2A-B55α activity and inhibits apoptosis by interacting with AIF.

Conclusions:

  • The LIV-1-GRPEL1 axis is a key regulator of both mitotic exit and apoptosis.
  • Dysregulation of this axis is common in human epithelial cancers, suggesting its therapeutic relevance.
  • This axis represents a novel mechanism for determining cell fate following mitotic damage.

Related Concept Videos

The Cell Cycle Control System01:28

The Cell Cycle Control System

The cell cycle regulation directs how a cell proceeds from one phase to the next and begins mitosis. The cell cycle control system includes intracellular regulatory molecules and external triggers. They provide "stop" or "advance" signals and operate at specific cell cycle stages termed checkpoints to ensure that a particular process is completed before the cell advances to the next phase.
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...
5.2K
The Cell Cycle Control System02:11

The Cell Cycle Control System

The cell cycle is an organized set of events that leads the cell to divide into two daughter cells, each containing chromosomes identical to the parent cell. It is the cell cycle that leads to the formation of an entire organism from a single-cell zygote. Besides, cell division also functions in the renewal or repair of tissues in adult multicellular eukaryotes. For example, in the bone marrow, the stem cells divide to form new blood cells. Although essential for several functions, cell...
13.8K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.6K
Cells Coordinate Growth and Proliferation02:36

Cells Coordinate Growth and Proliferation

Cell size is a significant factor impacting cellular design, function, and fitness. There exists some internal coordination by which cells double their masses before division, thus, achieving homeostasis. Coordination between cell growth and proliferation depends on the checkpoints in between cell cycle phases. Loss of coordination or failure in the checkpoint mechanism can drive the cell to uncontrolled growth and loss of cellular function. Like dividing cells that coordinate cellular growth,...
5.0K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
38.2K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.9K