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CELL CYCLE REGULATION

Cdc2 (p34) [Cdk-1] - has the catalytic subunit of maturation-promotinf factor, and other subunit being a B-cyclin; Cdc2+B-cyclin is critical in the G2/M transistion; phosphorylation of Cdc2 at thr161 leads to the stabilization Cdc2+B-cyclin complex; phosphorylation of Cdc2 at tyr-15 by Wee1 protein kinase, leads to the inactivation of Cdc2; full activation of Cdc2+B-ctclin complex occurs only after termination od DNA synthesis, when Cdc25, a specific protein phosphatase, dephosphorylates tyr-15 and tyr-14 of Cdc2

Cdk2 (p33) - cyclin-dependent kinase is regulated by phosphorylation in similar fashion as cdc2; can associate with A, E, D1, D3 cyclins; complex Cdk2+A-cyclin is present in S and G2 periods, it is associated with DNA in the initiation complex during replication; but complex cdc2+A-cyclin is present only in G2; copmlex Cdk2+E-cyclin is active in the G1 and S-phases and is important for the progression from G1 to S

Cdk3 - regulated by p35

Cdk4 - cyclin-dependent kinase which associates with cyclins D1, D2, D3; activity of this kinase is regulated by phosphorylation of specific treonine residues; active cdk4+D1-cyclin complex can phosphorylate of retinoblastoma gene product (pRb)

Cdk5 - (p35) is localised in brain, in other tissues it is expressed in a truncated form, designated p25

Cdk6 - involved in G1 to S progression, complex Cdk4+D-cyclins can regulate phosphorylation pRb

Cdk7 - binds H-cyclin; this complex is required for phosphorylation of the complex Cdc2+B-cyclin, that is necessary for G2/M transistion; can also phosphorylate Cdk2, Cdk4 on specific regulatort treonine sites; can functioning as a TFIH subunit by phosphorylation the C-terminal domain of the lagerst subunit of RNA polymerase

Cdc16 - it is localised in the mitotic spindle centrosome; maybe it is required for cyclin degradation

Cdc34 - is required for the late G1-S transistion; this is ubiquitin-conjugating ligand; takes part in ubiquitination of G1 cyclins

p14 -

p15 - a member of p16 family, strondly upregulated by TGF-beta

p16 - inhibitor of Cdk4+D-cyclins interferes followed by preventation phosphorylation of pRb by Cdk4+D-cyclins

p18 -

p19 -

p21 (Cip1) - inhibitor of cdk activity in a quaternary complex that also included cyclin D, Cdk4, PCNA; p21 can bind and inhibit each member of cdk family; p21 can directly bind to PCNA and inhibit DNA replication

p27 (Kip1) - inhibitor of cdk; can bind to Cdk4+D-cyclin (preferentially), Cdk2+E-cyclin, Cdk2+A-cyclin and inhibit their cdk activity;  in normal cells p27 is gradually reduced when cells reach S-period, but TGF-beta can prevent this followed the cell arrest in G1-phase; important for G1-S transistion

p35 - is Cdk5

p53 - can activate p21

p107 - contains region which is similar to that in pRb, pRb2 and which can associate with E2F transcription factor

pRb - (p110) retinoblastoma gene product nuclear phosphoprotein which undregoes differential phosphorylation during the cell cycle; a number of cellular proteins interact with hypophosphorylated pRb including: E2F transcription factor, several cyclins, RBP-1, RBP-2, c-myc, N-myc, p46; during G1-phase pRb is predominantly hypophosphorylated state and it becomes increasingly phosphorylated through the cell cycle until late of mitosis when substantial dephosphorylation occurs

pRb2 - protein 120 kDa which shows a high degree of identifywith pRb and related p107 protein; contains region binding E2F transcription factor

MDM2 - can function to bind p53 and thereby block p53-mediated transactivation of cotransfected reporter constructs, to limit the length p53-mediated growth arrest following DNA damage

FAS (APO 1; CD-95) - FAS ligands (FAS-L) and tumor necrosis factors (TNFs) function as rapid inducers of cell deth; both of these ligands mediate their effects throughstructurally related receptors belonging th the TNF-R superfamily of type II receptors; FAS and TNF-R1 (receptor) share a unique cytoplasmic motif coined the “deth domain”, three additional proteins TRADD, FADD, RIP also contain “deth domain”

TRAIL (APO-2) - TNF-related apoptosos inducing ligand belongs TNF family member, rapidly induces apoptosis

FAF1 - FAS-associated factor specifically interacts with cytoplasmic domain FAS and potentiates FAS-induced apoptosis

CAS (p100)  - cellular apoptosis susceptibility; plays an important role in both toxin and TNF mediated cell death, as well as in cell proliferation; CAS expression increases when resting cells are induced to proliferate and decrease when they are growth arrested

 Bcl-2 - blocks cell death following a variety of stimuli

Bax (p21) - form a complex with Bcl-2; overexpression of ob Bax accelerates apoptotic cell death

Bcl-xL - belongs to Bcl/Bax family; represses cell death, while its short form Bcl-xS  favors cell death

Bad  - belongs to Bcl/Bax family; selectively dimerizes with Bcl-xL , as well as with Bcl-2; Bad binds more strongly to Bcl-xL  than to Bcl-2 and reverses the death repressor activity of Bcl-xL but not of Bcl-2

Bcl-w - belongs to Bcl/Bax family;

A1 related protein (Bfl-1) - belongs to Bcl/Bax family;

Bag-1 - belongs to Bcl/Bax family; Bcl-2 binding protein; anti-death;

CYCLINS

PCNA - proliferating cell nuclear antigen; ia auxillary protein of DNA polymerase sigma; is synthesized in early G1 and S-phases

cyclin D1 - (product of PRAD1 or BCL1 gene) is synthesized in late G1 and appears to be required for progression into S-phase; overexpression of D1-cyclin leads to the reduction of length of G1

cyclin D3 - can associate with Cdk5 and weakly with Cdk2; function is not so clear; in T-cells, where D1-cyclin is absent, D3-cyclin binds Cdk4; while the D-type cyclins are associated with cdk, these can bind PCNA

cyclin A - is required for S-pase and passage through G2; disruption of normal cyclin A expression will cause cells to arrest at G2; binds Cdk2 near the start of S-phase; may be necessary for the initiation of DNA prelication

cyclin C - maybe, it can activate Cdc2 or a related Cdk at the G1 restriction point

cyclin E - activates Cdk2 near the start of S-phase, to be necessary for the initiation of DNA replication - S-phase

cyclin B - is a critical regulator of mitosis; associate with inactive Cdc2; inactive complex Cdc2+B-cyclin is accumulated until the end of G2, then Cdc2 is phosphrylated by p25 at thr-14 and thr15 and the complex appears to be active and the cell grive into M-phase; this complex remains active until methaphase/anaphase when cyclin B becomes degraded; this degradation process appears to be  ubiqutin-dependent and is necessary for the cell exit mitosis

cyclin H - binds Cdk7, complex Cdk7+H-cyclin phosphorylates Cdc2 in complex with B-cyclin followed passing the cell from G2 to M-phase

KAP - is a protein phosphatase, can bind Cdk2 and Cdc2 and regulate phosphorylation of these

JAK1 - is required for the phosphorilation og the transcription factor Stat1 (p91) in responce to INF-alpha or gamma, and for phosphorilation of Stat2(p113) in response to INF-alpha

GADD Genes -  p53 can upregulate expression GADD45, which inhibits entry of cells into S-phase and apparently acts in concert with GADD153 in inducing growth arrest; expression of GADD153 is increased after DNA damage and independent of p53

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