Cell Cycle Control

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.

Cyclins/Cdks

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

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 p27^Kip1 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 p21^waf1/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 HPVE7 prevents G1 arrest.

Modulation of expression of p21^waf1/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 tumor supressor gene 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 Rb in response to extracellular mitogens

p53 promotes transcription of genes that induce cell cycle arrest (especially p21) or apoptosis in response to DNA damage or other cell stress. Its expression is often elevated subsequent to induction of 053 activity. it is a classic tumor suppressor gene.

         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 DNA tumor viruses, including adenovirus E1B 55 kD protein, SV40 T antigen, and HPV E6, also bind to p53 and prevent apoptosis.

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 pRb 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 p15^INK4B.

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