BCECF-AM br Conclusions Taken together the roles of CDK and
Conclusions Taken together, the roles of CDK8 and miR-152-3p in the process of HCC likely performed opposite effect completely. Both CDK8 and miR-152-3p could serve as the independent prognostic factors for predicting the OS and DFS in HCC patients. We identified that miR-152-3p as a post-transcriptional regulator of CDK8 might possess favorable pharmacologic properties to prevent the progression of HCC.
Introduction Cell cycle dysregulation resulting in mitogenic signaling and leading to uncontrolled proliferation is one of the hallmarks of cancer , , , . Cyclin-dependent kinases (CDKs), a family of serine/threonine protein kinases are known to play a vital role in BCECF-AM regulation and modulate transcription activity , . Unlike other kinases, CDKs require cyclin (a protein subunit) that provides additional sequences for enzymatic activity . Till date, 20 subfamilies of CDKs are known; three (CDK1, 4 and 5) are involved in cell cycle, and five (CDK 7, 8, 9 and 11) are associated with transcription , , . In brief, all the CDKs have a two-lobed structure-N-terminal having beta sheets and C-terminal composed of α-helices. N-terminal lobe contains G-loop (rich in glycine) inhibitory component, and C-terminal contains activation segment that also includes phosphorylation residues; serine or threonine (known as T-loop in the case of CDKs) (Fig. 1). The role of various CDKs in the cell cycle progression is represented in Fig. 2. Briefly, p53 which is an important regulator of both G1/S, and G2/M checkpoint interacts with cyclin B and CDK1 . After that cell enters early G1 phase, which is mitogen dependent and acted upon by cyclin D in conjugation with CDK 4 and 6 . The growth factors are required to play their role at this point. Once the cell progress pasts the restriction point, mitogens are no longer needed for cell cycle progression. Cyclin D in conjugation with CDK4 and 6 promotes and ensures the cell progression beyond the limit point by phosphorylating and thus inhibiting retinoblastoma (RB), which allows E2F-mediated S-phase gene transcription , . The cell then enters S-phase where DNA replication occurs. The G1/S checkpoint allows checking of DNA integrity before cell DNA is replicated. Cyclin A and CDK1, 2 play a vital role in S phase. CDK inhibitors thereby halt the progression of the cell cycle by inhibiting the cyclins and the CDKs. They act at multiple phases of cell cycle primarily at G1/S and G2/M checkpoints. Activation of CDK involves binding of CDKs with their respective cyclins at the C-terminal via noncovalent interactions and leads to the accessibility of ATP to the catalytic site for phosphorylation of threonine. A list depicting the association of cyclins with CDKs and their overexpression in various cancers has been presented in Table 1. Some of the CDKs do not require cyclin for activation; for instances, such as viral cyclins (cyclins from a virus), CDK5 activators (p35 and p39 have no homology with cyclins), RINGO/Speedy family (small proteins with no homology to cyclins) , . The endogenous ligands that activate the CDKs are mainly cyclins. These are classified as cyclin A, cyclin B, cyclin C, cyclin D, cyclin E, cyclin F, cyclin H, cyclin K, cyclin L and Cyclin T. These cyclins play a significant role in cell cycle progression by activation of ATP binding site. Cyclin A forms a complex with CDK1 and CDK2 and helps in the regulation of S phase , . Cyclin B is also called as maturation or mitosis promoting factor as it forms complex with CDK1 and controls the M phase of the cell cycle , . Cyclin C and H activate CDK8 which in turn plays a significant role in RNAPII transcription and also inhibits the lipogenesis , . Cyclin D in complex with CDK4 and CDK6 controls the G1 phase of cell cycle . Cyclin E helps in the Rb/E2F transcription via formation of a complex with the CDK2 and controls G1-S phase . Cyclin K helps in the RNAPII transcription by forming a complex with CDK12 and CDK13 , , . Cyclin L and CDK11 associate to perform RNA splicing. Cyclin T with CDK9 plays a major role in RNAPII transcription . Cyclin Y/CDK14 drives the Wnt/β-catenin pathway .