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Cell cycle Role of SCF complex in cell cycle regulation

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Cell cycle Role of SCF complex in cell cycle regulation

Role of SCF complex in cell cycle regulation

The events controlling cell division are governed by the degradation of differentregulatory proteins by the Ubiquitin -dependent pathway. Ubiquitin, asmall protein of 76 amino acids is found in all eukaryotic cells. In the Ubiquitin-dependent pathway, the attachment of a polyubiquitin chain to a substrate is realized byan ubiquitin-ligase targets this substrate for degradation by the 26S proteasome. Theubiquitination pathway sequentially involves the E1 Ub-activating enzyme, E2Ub-conjugating enzymes, and E3 Ub-ligases [1].

E1 Ub-activating enzyme (e.g. ubiquitin-activating enzyme E1 ( UBE1 ))activates Ubiquitin in the ATP-dependent manner [2] and transfers itto E2 Ub-conjugating enzyme through thioester bond formation. E2 Ub-conjugating enzyme(e.g. cell division cycle 34 ubiquitin-protein ligase ( CDC34 )) activatesubiquitin-polymerization [3]. E3 Ub-ligase mediates the transfer ofUbiquitin from E2 Ub-conjugating enzyme to the substrate protein [1].

S-phase kinase-associated protein 1 p19 ( SKP1 )/ Cullin/F-box complex (SCF complex) is one of E3-ubiquitin ligases, which play a very important role inthe cell cycle. SCF complex consists of Cullin 1, SKP1, F-boxproteins (e.g. S-phase kinase-associated protein 2 p45 ( Skp2 ), beta-transducinrepeat containing protein ( TrCP ) or F-box protein FBW7 ( FBXW7 )) andRING-box protein 1. The Cullin 1/ RING-box protein 1 componentsare associated with E2 Ub-conjugating enzymes [1]. Ubiquitin-lake proteinNEDD8 charged surface residues mediates activation of Cullin 1/RING-box protein 1, which is needed to specifically support Cdc34-catalyzed ubiquitin polymerization [3]. F-box proteins directly recruitubiquitination substrates and bridge the interaction between E2 Ub-conjugating enzyme andthe substrate [1].

SCF complex participates in cell cycle regulation by stimulating ubiquitinationof the cell cycle proteins and their degradation by the 26S proteasome. Most substratesrequire phosphorylation to interact with the F-box protein in an SCF complex[1].

Cell division cycle 25A phosphotase ( CDC25A ), Cyclin D, CyclinE, cyclin-dependent kinase 2 ( CDK2 ), DNA replication factor ( Cdt1), cyclin-dependent kinase inhibitor 1A ( p21 ), cyclin-dependent kinase inhibitor1B ( p27KIP1 ), E2F transcription factor 1 ( E2F1 ) and retinoblastoma-like2 ( p130 ) bind to SCF complex and degrade during interphase [4], [1].

CDC25A is phosphorylated by some kinases in response to DNA damage (e.g. cellcycle checkpoint kinase 1 ( Chk1 ). Phosphorylated CDC25A is ubiquitinatedby SCF complex in late S and G2 phases [5]. Stimulation of thegrowth factor beta (TGF-beta)/ SMAD family member 3 ( Smad3 ) pathway promotesSCF complex- mediated CDC25A ubiquitination [6]. Moreover,SCF complex may promote ubiquitin-proteasome degradation of Smad3 [7].

Phosphorylated by cyclin-dependent kinases (e.g. cyclin-dependent kinase 4 (CDK4 )) p130 is ubiquitinated by SCF complex in G1 phase [8].

CDK2 binds to SCF complex and is degraded during late S or G2 phase. Atthe same time, phosphorylation of p27KIP1 [9], Cyclin E[10] and Cdt1 [11] by CDK2 promotes their SCFcomplex- mediated destruction during G1 and S phases [1]. Ubiquitinationof p27KIP1 requires the SCF complex and Skp2 F-box binding proteinCKS1 [12], [13].

Cyclin D1 [14] and p21 bind to the SCF complex andget degraded during interphase too [15].

Tyrosine kinase Wee1 and F-box protein 5 ( Emi1 ) bind to SCFcomplex and degrade during mitosis.

Major M-phase kinases Polo-like kinase 1 ( Plk1 ) and Cdk1 phosphorylateWEE1 [16] and Emi1 [17], [18]. Thephosphorylation makes WEE1 and Emi1 accessible to SCF complex-mediated degradation . Emi1 promotes S phase entry in somatic cells byinhibiting the APC/hCdh1 complex [19].