Restriction point
Encyclopedia
The restriction point is a G1 phase
checkpoint
in the cell cycle
of animal
cell
s. Prior to the restriction point, a cell exits the cell cycle if specific mitogenic and growth signals are absent. Cells that progress past the restriction point are committed to enter S phase
, where DNA synthesis
and replication
occurs. Yeast
cells contain a similar checkpoint, termed the START point
.
demonstrated that a single restriction point exists for a variety of proliferative and antiproliferative inputs. These inputs are integrated in a single switch, termed the restriction point, that regulates the reentry of a cell into a new round of the cell cycle.
Lack of growth factor
s causes some cells to arrest prior to the restriction point. In 1985, Zetterberg and Larsson discovered that, in all stages of the cell cycle, serum deprivation results in inhibition of protein synthesis except in postmitotic cells in the first 3-4 hours of G1. If external conditions are not appropriate for S phase, then the cell may enter G0 phase
, a quiescent
stage. Pardee also demonstrated that the restriction point is defective in cancer cell lines, providing physiological relevance for this molecular switch. Mutation
s in factors contributing to cell cycle
arrest at the restriction point are thought to be the main contributors to cancer
.
to S phase
involves the phosphorylation and inactivation of the retinoblastoma protein
(Rb), which leads to activation of a positive feedback loop that involves E2F
, pRb, and cyclin E
. E2F activates the transcription of several genes involved in DNA replication and S phase progression.
The feedback loop centered on E2F activation exhibits bistability
upon serum stimulation or starvation. Once a threshold level of E2F expression is reached, removal of serum is insufficient to revert to a quiescent state, and the cell will continue progression through the cell cycle independent of external signals. Rb/Cyclin E/E2F positive feedback is important for driving progression from G1 to S; its involvement in the restriction point has yet to be determined.
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
checkpoint
Cell cycle checkpoint
Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase...
in the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
of animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s. Prior to the restriction point, a cell exits the cell cycle if specific mitogenic and growth signals are absent. Cells that progress past the restriction point are committed to enter S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
, where DNA synthesis
DNA synthesis
DNA synthesis commonly refers to:*DNA replication - DNA biosynthesis *Polymerase chain reaction - enzymatic DNA synthesis *Oligonucleotide synthesis - chemical synthesis of nucleic acids...
and replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
occurs. Yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
cells contain a similar checkpoint, termed the START point
Start Point
Start Point may refer to:*Start Point, Devon, in England*Start Point, Cornwall in Cornwall, England*Start Point, Livingston Island on Livingston Island*Start Point, Sanday, in the Orkney Islands, Scotland...
.
Discovery of the restriction point
In 1974, Arthur PardeeArthur Pardee
Arthur Pardee is an American biochemist. One biographical portrait begins "Among the titans of science, Arthur Pardee is especially intriguing." There is hardly a field of molecular biology that is not affected by his work, which has advanced our understanding through theoretical predictions...
demonstrated that a single restriction point exists for a variety of proliferative and antiproliferative inputs. These inputs are integrated in a single switch, termed the restriction point, that regulates the reentry of a cell into a new round of the cell cycle.
Lack of growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s causes some cells to arrest prior to the restriction point. In 1985, Zetterberg and Larsson discovered that, in all stages of the cell cycle, serum deprivation results in inhibition of protein synthesis except in postmitotic cells in the first 3-4 hours of G1. If external conditions are not appropriate for S phase, then the cell may enter G0 phase
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...
, a quiescent
Quiescence
Quiescence may refer to:*Quiescence search, in Game searching in artificial intelligence, a quiescent state is one in which a game is considered stable and unlikely to change drastically the next few plays...
stage. Pardee also demonstrated that the restriction point is defective in cancer cell lines, providing physiological relevance for this molecular switch. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in factors contributing to cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
arrest at the restriction point are thought to be the main contributors to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Genes involved in the G1/S transition
The transition from G1 phaseG1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
to S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
involves the phosphorylation and inactivation of the retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(Rb), which leads to activation of a positive feedback loop that involves E2F
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...
, pRb, and cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
. E2F activates the transcription of several genes involved in DNA replication and S phase progression.
The feedback loop centered on E2F activation exhibits bistability
Bistability
Bistability is a fundamental phenomenon in nature. Something that is bistable can be resting in either of two states. These rest states need not be symmetric with respect to stored energy...
upon serum stimulation or starvation. Once a threshold level of E2F expression is reached, removal of serum is insufficient to revert to a quiescent state, and the cell will continue progression through the cell cycle independent of external signals. Rb/Cyclin E/E2F positive feedback is important for driving progression from G1 to S; its involvement in the restriction point has yet to be determined.