cell cycle Flashcards
S phase
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 event in eukaryotes are highly conserved.
S phase regulation
The G1/S transition is a major checkpoint in the regulation of the cell cycle. Depending on levels of nutrients, energy and external factors, cells must decide to enter the cell cycle or move into a non-dividing state known as G0 phase. This transition, as with all of the major checkpoint transitions in the cell cycle, is signaled by cyclins and cyclin dependent kinase (CDKs).
M phase
Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.
G1
In this part of interphase, the cell grows in size and synthesizes mRNA and proteins in preparation for subsequent steps leading to mitosis. G1 phase ends when the cell moves into the S phase of interphase . G1 phase is particularly important in the cell cycle because it determines whether a cell commits to division or to leaving the cell cycle. If a cell is signaled to remain undivided, instead of moving onto the S phase, it will leave the G1 phase and move into a state of dormancy called the G0 phase. Most nonproliferating vertebrate cells will enter the G0 phase.
G2
G2 phase is a period of rapid cell growth and protein synthesis during which the cell readies itself for mitosis. Curiously, G2 phase is not a necessary part of the cell cycle, as some cell types (some cancers) proceed directly from DNA replication to mitosis.
restriction point
a point in G1 of the animal cell cycle at which the cell becomes “committed” to the cell cycle and after which extracellular proliferation stimulants are no longer required. Cyclin D-bound cdk’s 4 and 6 are activated by cdk-activating kinase and drive the cell towards the restriction point. Cyclin D, however has a high turnover rate. It is because of this quick turnover rate that the cell is extremely sensitive to mitogenic signaling levels, which not only stimulate cycin D production, but also help to stabilize cyclin D within the cell. In this way, cyclin D acts as a mitogenic signal sensor. Cdk inhibitors (CKI), such as the Ink4 proteins and p21, help to prevent improper cyclin-cdk activity. Active cyclin D-cdk complexes phosphorylate retinoblastoma protein (pRb) in the nucleus. pRb acts as an inhibitor of G1 by preventing E2F-mediated transcription. Once phosphorylated, E2F activates the transcription of cyclins E and A. Active cyclin E-cdk begins to accumulate and completes pRb phosphorylation
Cyclin-dependent kinases (CDKs)
a family of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells.. The CDK subunit is inactive and requires binding of the cyclin subunit for activity in order to permit ATP binding. It is cyclin protein levels that change to regulate CDK activity during the cell cycle. Full kinase activity requires an activating phosphorylation by CDK-activating kindase (CAK) on a threonine adjacent to the active site. Another level of regulation is the binding of CDK inhibitors. CDKs phosphorylates either serine, threonine or proline
cyclin-dependent kinase inhibitor protein (CDI)
a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA. Several function as tumor suppressor genes. Cell cycle progression is negatively controlled by cyclin-dependent kinases inhibitors (called CDIs, CKIs or CDKIs). CDIs are involved in cell cycle arrest at the G1 phase. In animal cells, there are two major CKI families: the INK4 family and the CIP/KIP family
Where and when do cyclins act on the cell cycle?
Cycling cells undergo three major transitions during their cell cycle. The beginning of S phase is marked by the onset of DNA replication, the start of mitosis (M) is accompanied by breakdown of the nuclear envelope and chromosome condensation, whereas segregation of the sister chromatids marks the metaphase-to-anaphase transition. Cyclin-dependent kinases (CDKs) trigger the transition from G1 to S phase and from G2 to M phase by phosphorylating distinct sets of substrates. CDK1 and CDK2 bind to multiple cyclins (cyclin types A, B, D and E), whereas CDK4 and CDK6 only partner D-type cyclins. According to the classical model of cell cycle control, D-type cyclins and CDK4 or CDK6 regulate events in early G1 phase, cyclin E-CDK2 triggers S phase, cyclin A-CDK2 and cyclin A-CDK1 regulate the completion of S phase, and CDK1-cyclin B is responsible for mitosis. Accordingly, either CDK1 or CDK2 bound to cyclin A is sufficient to control interphase, whereas cyclin B-CDK1 is essential to take cells into mitosis.
Ras
A growth factor that can induce cyclinD production
somatic cell cycle
the cell cycle can be divided in three periods: interphase—during which the cell grows, accumulating nutrients needed for mitosis preparing it for cell division and duplicating its DNA—and the mitotic (M) phase, during which the cell splits itself into two distinct cells, often called “daughter cells” and the final phase, cytokinesis, where the new cell is completely divided. Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals
Rb (Retinoblastoma protein)
Rb restricts the cell’s ability to replicate DNA by preventing its progression from the G1 (first gap phase) to S (synthesis phase) phase of the cell division cycle. Rb binds and inhibits transcription factors of the E2F family, which are composed of dimers of an E2F protein and a dimerization partner (DP) protein. The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase. As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When Rb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle. The Rb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis. p107 and p130 are Rb-like proteins and can not substitute in the retina
Cip/Kip
includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. These proteins inhibit CDK1-6
INK4
a tumour suppressor protein. Lack of this protein has been associated with several types of cancer, including bladder and melanoma. The ‘INK4’ label is given to three proteins: INK4A and INK4B. These proteins act to inhibit cdk4 and cdk6 upon binding, causing the arrest of the cell cycle in G1. Includes p15, p16, p18, p19
p27
binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle. It belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins.
p21
a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase. In addition to growth arrest, p21 can mediate cellular senescence. One of the ways it was discovered was as a senescent cell-derived inhibitor. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli
p15
a cyclin-dependent kinase inhibitor, also known as p15Ink4b protein, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases by cyclin D, thus functions as a cell growth regulator that inhibits cell cycle G1 progression.
p16
a cyclin-dependent kinase (CDK) inhibitor that slows down the cell cycle by prohibiting progression from G1 phase to S phase. p16 acts as a tumor suppressor by binding to CDK4/6 and preventing its interaction with cyclin D. This interaction ultimately inhibits the downstream activities of transcription factors, such as E2F1, and arrests cell proliferation. is also a tumor suppressor in melanoma and other cancers (e.g. non-small cell lung cancer, head and neck cancer).
CDK4/6-cyclinD complexes
CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB). Once phosphorylated, pRB disassociates from the transcription factor E2F1, liberating E2F1 from its cytoplasm bound state allowing it to enter the nucleus. Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase.
Mitiogens
also called growth factors eventually will cause the production of cyclinD1-3 that activates CDK4/6 to inhibit Rb, resulting in entry into the cell cycle and S phase ensues. Mitogens act at the cell surface and ultimately cause an increase in cyclin D1 transcription, which results in an increase in cyclin D1-3 proteins and more CDK4/6-cyclin D1-3 active protein kinase complexes
cyclin D
form holoenzymes with cyclin-dependent protein kinases (Cdk), which they activate. The abundance of cyclins is generally regulated by protein synthesis and degradation through an APC/C dependent pathway. In proliferating cells, cyclin D-Cdk4/6 complex accumulation is of great importance for cell cycle progression. Namely, cyclin D-Cdk4/6 complex partially phosphorylates retinoblastoma tumor suppressor protein (Rb), whose inhibition can induce expression of some genes (for example: cyclin E) important for S phase progression.
