ZNF768 links oncogenic RAS to cellular senescence
Romain Villot1,2, Audrey Poirier1,2, Inan Bakan1,2
1Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval, Québec, QC, Canada.
Nature Communications
|August 18, 2021
Summary
ZNF768 protein levels decrease with RAS activation, impairing cell proliferation and inducing senescence. Overexpression of ZNF768 bypasses senescence by repressing the p53 pathway, promoting tumor growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- RAS GTPases are crucial regulators of cell fate, influencing proliferation and senescence.
- The precise mechanisms integrating RAS signaling to balance cell division and senescence remain unclear.
Purpose of the Study:
- To identify novel regulators of the balance between cell proliferation and senescence.
- To elucidate the role of ZNF768 in RAS-mediated cell fate decisions.
Main Methods:
- Investigated ZNF768 protein stability and expression in response to RAS activation.
- Assessed the impact of ZNF768 depletion and overexpression on cell proliferation and senescence.
- Analyzed ZNF768 interaction with and regulation of the p53 pathway.
- Examined ZNF768 expression in human tumors using cancer genomics and immunohistochemistry.
Main Results:
- ZNF768 is a phosphoprotein destabilized by RAS activation.
- ZNF768 depletion induces senescence by affecting cell cycle regulators and p53 targets.
- ZNF768 levels decline during replicative, stress, and oncogene-induced senescence.
- ZNF768 overexpression bypasses RAS-induced senescence by inhibiting p53 phosphorylation and activity.
- ZNF768 is frequently amplified or overexpressed in tumors.
Conclusions:
- ZNF768 acts as a critical link between oncogenic RAS signaling and cell fate control.
- ZNF768 dysregulation contributes to senescence evasion, sustained proliferation, and malignant transformation.
- Targeting ZNF768 may offer therapeutic strategies for cancers driven by RAS pathway activation.
Related Concept Videos
02:38The Ras Gene
6.6K
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...
Ras is a...
6.6K
01:20The Retinoblastoma Gene
4.3K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.3K
02:26NF-κB-dependent Signaling Pathway
8.0K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
8.0K
02:15Replicative Cell Senescence
3.9K
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
3.9K
02:23Abnormal Proliferation
4.7K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.7K
01:24Small GTPases - Ras and Rho
4.4K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
4.4K