User:Shelbyfenton/sandbox

Mechanism
=== Initiation By Growth Factors === G1 phase progression is influenced by growth factors, however, after the interaction of RB and cyclin/CDK complexes occurs, the cell loses its dependence on growth factors.

In the presence of the appropriate growth factors the AKT pathway is triggered. When the AKT pathway is active, it inhibits the family of forkhead transcription factors (FOXO). FOXO has antiproliferative and pro-apoptotic effects. FOXO induces transcription of genes involved in cell cycle arrest, such as cyclin-dependent kinase inhibitors (CKIs), p21, p27KIP1 and p15INK4B. FOXO is also able to repress transcription of cyclin D. In the event that protein kinase B phosphorylates FOXO, FOXO translocates to the cytoplasm which prevents transcription of its target genes. FOXO then promotes cell survival and proliferation. By inhibiting the activity of FOXO the Akt pathway allows cell proliferation. In the presence of TGF-ß Smad3 is activated which suppresses cell progress before the G1/S phase checkpoint. In the event, where DNA damage is detected, the ATM/ATR pathway induces a rapid cascade. Depending on the type of DNA damage, ATM phosphorylates Chk2 kinases, while ATR phosphorylates Chk1 kinases. The main portion of this cascade is when Chk2/Chk1 triggers phosphorylation of the Cdc25A phosphatase, which causes Cdc25A ubquitination then demolition by the proteasome. Also, from DNA damage, the ATM/ATR pathway activation can cause the phosphorylation of p53. Phosphorylation stabilizes the p53 protein in the cell nucleus, which causes induction of the p21 CDK inhibitor. p21 is able to bind to cyclin E-CDK2, which inhibits the S phase promoter allowing for a G1 arrest. The inhibition of CDK2 also allows for dephosphorylation of Rb and thus inhibition of the E2F.

The CDK inhibitors are a major class of proteins involved in regulating the transition of the G1/S checkpoint. They are typically the effectors activated in response to damage. They have become increasingly well characterized having been tested in various biochemical assays, and recent attempts have been made to create a mathematical model of the mechanisms involved in the regulation of the restriction point. In the absence of growth factor, FoxO1/3 have been demonstrated to primarily activate three proteins: p15 INK4b, p27 Kip1 and p21 Cip1. When activated by FoxO1/3, P27, p21 and p15 inhibit cyclin-dependent kinase 2 and Cdk4/6 activity.

In the presence of activated AKT, the transcription of p15, p27 and p21 is down regulated and existing proteins are slowly deactivated, modulating the formation of CDK4/cyclin D complexes and CDK2/cyclin E complexes. Recent literature on the G1/S checkpoint suggests that CDK complex formation and activity may be modulated by a variety of other CDK inhibitors that are not controlled by FoxO, including p16, p18, p19 and p57. These FoxO independent CDK inhibitors are regulated by extracellular signals such as hormones, or by intracellular signals such as those indicative of DNA damage. The various inhibitors are typically divided into two categories: the INK/ARF CDK inhibitors which target CDK4 and 6 and the kip/cip CDK inhibitors which mainly target CDK2 and promote the formation of the CDK4 cyclin D complex. Another important protein involved in the regulation of CDKs is CDC25A, which has been found to activate CDK in response to Myc.