CDK1: A Potential Drug Target and Biomarker for Cell Cycle Control

Target Name: CDK1

NCBI ID: G983

CDK1

CDK1: A Potential Drug Target and Biomarker for Cell Cycle Control

Introduction

The cell cycle is a critical aspect of cell behavior, as it regulates various cellular processes, including DNA replication, protein synthesis, and cell growth. The cell cycle controller protein CDK1 is a key regulator of the cell cycle, and its dysfunction has been implicated in various diseases, including cancer. As a result, targeting CDK1 has become an attractive research topic in the field of biology and medicine.

CDK1: Structure and Functions

CDK1 is a 21-kDa protein that belongs to the family of the cyclin D-type kinases. CDK1 is expressed in most tissues of the body and plays a vital role in regulating the cell cycle. It is a key regulator of the G1 phase, G2 phase, and metaphase of the cell cycle, and it is involved in the transitions between these phases.

CDK1 functions as a negative regulator of the G1 phase, which means that it promotes the stay in G1 phase by inhibiting the activities of the cyclins that promote the transition from G1 to G2. During the G1 phase, CDK1 interacts with the cyclin D1, which is a G1-specific cyclin that binds to the CDK1 kinase domain. By binding to CDK1, CDK1 inhibits the activity of the cyclin-CDK complex, which leads to the accumulation of D1 at the G1-CDK interface, and the inhibition of the transition from G1 to G2.

CDK1 also functions as a positive regulator of the G2 phase, which means that it promotes the transition from G2 to M phase by activating the activities of the cyclins that promote the transition from G2 to M. During the G2 phase, CDK1 interacts with the cyclin A, which is a G2-specific cyclin that binds to the CDK1 kinase domain. By binding to CDK1, CDK1 activates the activity of the cyclin-CDK complex, which leads to the release of A from the CDK1-A interface and the transition from G2 to M phase.

CDK1 also plays a crucial role in the regulation of cell growth and the transition of cells from the G0 to the G1 phase. It has been shown that CDK1 inhibits the G0-to-G1 transition by promoting the accumulation of factors that promote cell growth, such as the protein kinase B (PKB).

CDK1 and Cancer

CDK1 has been implicated in the development and progression of many types of cancer, including breast, ovarian, and prostate cancers. Several studies have shown that CDK1 is overexpressed or hyperactive in cancer cells, and that its dysfunction is associated with cancer progression.

For example, a study by Kim et al. found that CDK1 was overexpressed in various types of cancer, including breast, ovarian, and prostate cancers. Another study by Zhang et al. found that CDK1 was associated with poor prognosis in patients with advanced stages of pancreatic cancer.

In addition to its role in cancer development, CDK1 has also been implicated in the regulation of cell proliferation. Several studies have shown that CDK1 is involved in the regulation of cell proliferation, and that its dysfunction is associated with the development of cancer.

CDK1 as a Drug Target

CDK1 has been identified as a potential drug target for cancer treatment. Several studies have shown that inhibiting CDK1 can lead to the inhibition of cell proliferation and the regression of cancer tumors.

One of the most promising strategies for targeting CDK1 is the use of small molecules that can inhibit its activity.

Protein Name: Cyclin Dependent Kinase 1

Functions: Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658, PubMed:26829474, PubMed:30704899). Required in higher cells for entry into S-phase and mitosis (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658). Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, KAT5, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2, CGAS and RUNX2 (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658, PubMed:32351706, PubMed:26829474, PubMed:30704899). CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs (PubMed:18480403, PubMed:20360007). Essential for early stages of embryonic development (PubMed:18480403, PubMed:20360007). During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation (PubMed:18480403, PubMed:20360007). Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis (PubMed:18480403, PubMed:20360007). Phosphorylates KRT5 during prometaphase and metaphase (By similarity). Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair (PubMed:20360007). Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression (PubMed:20395957). In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons (PubMed:18356527). The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis (PubMed:16371510). NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation (PubMed:19509060). In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis (PubMed:20171170). The phosphorylation of Bcl-xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis (PubMed:19917720). In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis (PubMed:20937773). This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes (PubMed:20937773). EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing (PubMed:20935635). CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration (By similarity). CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis (PubMed:26549230). Regulates the amplitude of the cyclic expression of the core clock gene BMAL1 by phosphorylating its transcriptional repressor NR1D1, and this phosphorylation is necessary for SCF(FBXW7)-mediated ubiquitination and proteasomal degradation of NR1D1 (PubMed:27238018). Phosphorylates EML3 at 'Thr-881' which is essential for its interaction with HAUS augmin-like complex and TUBG1 (PubMed:30723163

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