See also the Cell Cycle See also Cancer Disease Mechanisms

See also signal transduction

Controling the process of cell division is critical. Loss of this control can lead to cancer. 

The G1/S checkpoint is the primary point at which the cell decides to divide. This checkpoint is thus the primary point at which external signals can influence events of the cell cycle. As the G1/S checkpoint is approached, the triggering signal in yeast appears to be the accumulation of G1 cyclins. These form a complex with Cdc2 to create the active G1/S Cdk, which phosphoryaltes a number of targets that bring about the increased enzyme activity for DNA replciation. 

The primary molecular mechanism of cell cycle control is phosphorylation. The enzymes that accomplish this phosphorylation are the Cdks. Cdk is a protein kinase that activates numerous cell proteins by phosphorylating them. Cyclin is a regulatory protein required to activate Cdk. This complex is also called mitosis-promoting factor (MPF). The activity of Cdk is also controlled by the pattern of phosphorylation. Phosphorylation at one stie inactivates the Cdk, and phosphorylation at another site activates the Cdk. 

Mammalian cells answer to a wide range of extracellular growth factors, mitogen antagonists, differentiation inducers and spatial cues in exercising their commitment to enter S phase. Key regulators of G1 progression include three D-type cyclins (D1, D2, and D3) which assemble into holoenzymes with either cdk4 or cdk6 and cyclin E which combines later in G1 with cdk2.

Growth factors act by triggering intracellular signaling systems. Fibroblasts, for example, possess numerous receptors on their plasms membrane for platelet-derived growth factor (PDGF). The PDGF receptor is a receptor tyrosine kinase (RTK) that initiates a MAP kinase cascade to stimulate cell division. PDGF was discovered when investigaors found that fibroblasts would grwo and divide in tissue culture only if the growth medicum contained PDGF. 

Specific Regulators of the Cell Cycle:

Cyclins/Cdks

–D type cyclins/ Cdk4 & Cdk6: phosphorylate and inactivate pRB in response to mitogenic signals. 

–CDK4-CDK6 and the cell cycle: 

CDK4 and CDK6 are particularly relevant to oncogenesis because together with D type cyclins, they promote progression of the cell cycle from G1 phase to S phas.e One decade after their discovery, the small molecule palbociclib emerged as the first CDK4/CDK6 inhibitors to gain approval by the FDA. 

–CyclinE/Cdk2: activity is present briefly in the late G1 and early S phases and is critical for S-phase entry.

Protein kinases and protein phosphatases that modify Cdks

–Cdk-activating kinase (CAK) phosphorylates an activating site in Cdks 

–Wee1 kinase phosphorylates inhibitory sites in Cdks, primarily involved in controlling entry into mitosis

–Cdc25 phosphatases remove inhibitory phosphates from Cdks; 3 family members (Cdc25A, B, C) in mammals; Cdc25C is the activator of Cdk1 at the onset of mitosis

Cyclin-dependent Kinase Inhibitors (CdkIs) 

Sic1 (budding yeast) suppresses Cdk activity in G1; phosporylation by Cdk1 triggers its destruction

p27 is the product of the p27Kip1 gene. It suppresses G1/S-Cdk and S-Cdk activities in G1; helps cells to withdraw from cell cycle when they terminally differentiate; phosphorylation by cdk2 triggers its ubiquitylation by SCF

p21 is the product of the p21waf1/cip1 gene. It is a cdk inhibitor that suppresses G1/S-Cdk and S-Cdk activities following DNA damage in G1; Loss of cyclin-cdk activity in G1 phase prevents phosphorylation of pRb, and the hypophosphorylated pRb retains its ability to sequester E2F and prevents initiation of DNA synthesis. After DNA damage in cells with wild-type p53, pRb is found predominantly in the hypophosphorylated form. Abrogation of pRb activity by   prevents G1 arrest.

Modulation of expression of p21waf1/cip1 can be P53-dependent or P53-independent. p21 synthesis is increased when p53 is induced after DNA damage by ionizing radiation. By indirectly inhibiting cdk activity, p53 induction thereby prevents pRb phosphorylation and the release of E2F.

p16 is the product of the ink-4a gene. p16 suppresses G1-Cdk activity in G1; p16 is a which is frequently inactivated in cancer

Ubiquitin ligases and their activators

SCF catalyzes ubiquitylation of regulatory proteins involved in G1 control, including CKIs (Sic1 in buddying yeast, p27 in mammals); phosphorylation of target protein usually required for this activity)

Gene regulatory proteins

SCB and MCB yeast transcription factors that are activated by the G1 cyclins which in turn activate transcription genes required for S phase entry

Myc activates transcription of D type cyclins, SCF and E2F leading to increase E2F activity and S phase entry

E2Fs are a family of heterodimeric transcription regulators which can transactivate genes whose products are importnt for S phase entry. E2Fs promotes transcription of genes required for G1/S progression, including genes encoding G1/S cyclins, S-cyclins, and proteins required for DNA synthesis; stimulated by G1 Cdk; phosphorylates in response to extracellular mitogens

p53 promotes transcription of genes that induce cell cycle arrest (especially p21) or in response to DNA damage or other cell stress. Its expression is often elevated subsequent to induction of p53 activity. The TP53 gene, which is a tumor-suppressor gene, encods the p53 protein. Theis gene has been called the “guardian of the genome” because it is involved in the G/1S checkpoint, hwere damaged DNA causes p53 to pause the cell cycle to give the cell time to repair the damage. If the damage is severe enoguh, p53 will casue the cell to initiate apoptosis 

Mdm2 is the major negative regulatory of p53. Mdm2 promotes p53 degradation. It is a ubiquitin ligase that targets 053 to proteasomal degradation, thus defining a negative feedback loop to regulate p53 levels. Downregulation of Mdm2 trnascript by the catechin EGCG might preserve intact p53 protein. Mdm2 is itself a positive transcriptional target of p53. 

The transforming proteins of , including adenovirus E1B 55 kD protein, SV40 T antigen, and , also bind to p53 and prevent .

Growth Factors: Over 300 different peptides that appear to ahve grwoth factor activity have been identified. These can be grouped into mroe than 30 families of related peptides. A specific cell surface receptor recognizes each growth factor, its binidng site fitting that grwoth factor precisely. Tehse receptors often initiate MPA kinase cascades in which the final kinase enters the nucleus and activates transcription factors by phosphorylation. These transcription factors timulate the production of g1 cyclins and the proteins that are necessary for cell-cycle progression. 

The cellular selectivity of a particular grwoth factor depends on which target cells bear its unique receptor. Some grwoth factors, such as PDGF and EGF affect a broad range of cell types, but others affect only specific types. For example, nerve growth factor (NGF) promotes the growth of certain classes of neurons, and erythropoietin tiggers cell division in red blood cell precursos. Most animla cells need a comibnaiton of several different growth factors to overcome the various controls that inhibit cell division. 

Cytokines

TGF-B is the prototype member of a large superfamily of cytokines that exhibit diverse effects on cell proliferation. TGFB1 is the most extesnively studies member of the family and its antiprolifertive effects on many types of cells has been well documented. When administered in the G1 phase of the cell cycle, TGFB1 reversibly arrests cells in late 5!, by preventing phosphorylation of by cylin-cdk complexes. After progression from G1 to S phse, cells become unresponsive to the growth-inhibitory effects of TGFB1. Cell-cycle arest is primarily accomplished by either inhibition of cdk4 expression or induction of p15INK4B.