• CDKs are under inhibitory control of cyclin dependent kinase inhibitors (CDKIs). (biomedcentral.com)
  • The activity of CDKs is controlled by their binding to coactivator subunits termed Cyclins, as well as by CDK inhibitory proteins termed CKIs. (intechopen.com)
  • Cyclin-dependent kinase inhibitors (CDKIs) are proteins that bind to and inhibit the activity of CDKs. (biomedcentral.com)
  • The accumulation of both Cyclin and CKI proteins is tightly regulated at the level of transcription. (intechopen.com)
  • In addition, Cyclin and CKI proteins are controlled at the level of their destruction. (intechopen.com)
  • New regulatory targets were discovered and novel functions of known proteins were uncovered. (janechin.net)
  • The ENCODE, for the Encyclopedia of DNA Elements , project was a five-year collaboration of more than 440 scientists in 32 labs around the world to reveal the complex interplay among regulatory regions, proteins and RNA molecules that governs when and how genes are expressed. (pharmaceuticalintelligence.com)
  • They studied 128 proteins, called trans-acting factors , which are known to regulate gene expression by binding to regulatory regions within the genome. (pharmaceuticalintelligence.com)
  • Before our work, only the combination of two or three regulatory proteins were studied, which oversimplified how gene regulators collaborate to find their targets," Xie said. (pharmaceuticalintelligence.com)
  • ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1. (babraham.ac.uk)
  • ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. (babraham.ac.uk)
  • Our results suggest that ERKi, including current clinical candidates, act as 'kinase degraders', driving the proteasome-dependent turnover of their major target, ERK2. (babraham.ac.uk)
  • Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. (bvsalud.org)
  • Cyclins and CDKs assemble into complexes with one another as cells progress through G1 phase, cyclins being required to activate the serine-threonine kinase activity of their catalytic partners. (biomedcentral.com)
  • This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). (babraham.ac.uk)
  • The progression of cells through the cell cycle is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). (biomedcentral.com)
  • The basic unit of the p53 protein consists of three major functional domains such as an N-terminal transactivation domain (TAD), a core DNA-binding domain (DBD)-the main target for mutations, and a C-terminal regulatory domain (CTD) ( Figure 1 A) [ 2 ] . (encyclopedia.pub)
  • However, recent studies have suggested that BRAFi/MEKi and ERK1/2i resistance can arise through activation of a parallel signalling pathway leading to activation of ERK5, an unusual protein kinase that contains both a kinase domain and a transcriptional transactivation domain. (babraham.ac.uk)
  • Cyclins regulate the cell cycle in association with cyclin dependent kinases (CDKs). (biomedcentral.com)
  • Cyclins function as the positive regulators of CDKs. (biomedcentral.com)
  • D-type and E-type cyclins assemble with CDKs during the G1 phase and these holoenzymes act as rate-limiting controllers to regulate passage through the restriction point and the subsequent onset of DNA replication [ 2 , 3 ]. (biomedcentral.com)
  • Progression through the cell cycle is driven by the oscillating activity of Cyclin Dependent Kinases (CDKs). (intechopen.com)
  • Growth factors that signal through tyrosine-kinase receptor families include the epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and transforming-growth factor-α (TGF-α). (janechin.net)
  • Transforming growth factor-β1 (TGF-β) signals through a serine/threonine-kinase receptor pathway. (janechin.net)
  • Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through gene amplification and can be suppressed by impeding cell cycle entry in drug. (babraham.ac.uk)
  • Activation of each phase is dependent on the proper progression and completion of the previous one. (wikipedia.org)
  • These resistance mechanisms frequently involve reinstatement of ERK1/2 signalling and BRAFi are now deployed in combination with one of three approved MEK1/2 inhibitors (MEKi) to provide more durable, but still transient, clinical responses. (babraham.ac.uk)
  • However, limited clinical progress has been achieved with PIKfyve inhibitors. (bvsalud.org)
  • This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi. (babraham.ac.uk)
  • The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. (bvsalud.org)
  • Importantly, PIK5-12d was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. (bvsalud.org)
  • PCNA is a co-factor of cyclin-D and it makes a complex with cyclin-D, a cyclin dependent kinase (CDK), and a cyclin dependent kinase inhibitor (CDKI). (biomedcentral.com)
  • Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. (babraham.ac.uk)
  • D-type cyclins are usually synthesized by mid-G1 phase and accumulate to a maximum as cells advance through the G1/S boundary. (biomedcentral.com)
  • Here, we investigate amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that amplifications acquired are the primary cause of resistance. (babraham.ac.uk)
  • The p21 family (p21, p27, p28 and p57) can bind to broad range of CDK-cyclin complexes and inhibit their activities. (biomedcentral.com)
  • A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. (bvsalud.org)
  • They can bind and inhibit a broad range of cyclin/Cdk complexes, with a preference for those containing Cdk2 ( 17, 18 ). (aacrjournals.org)
  • In yeast, for instance, cell growth induces accumulation of Cln3 cyclin , which complexes with the cyclin dependent kinase CDK2. (wikipedia.org)
  • During early S-phase, the cyclin E-Cdk2 complex phosphorylates NPAT , a nuclear coactivator of histone transcription. (wikipedia.org)
  • Apoptosis-related genes (bad, bax, and bcl2), and cell cycle-related genes (cdk2, pcna, p27, and p57) showed remarkable increases in transcriptional level by RT-PCR. (biomedcentral.com)
  • The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. (bvsalud.org)
  • These three CKIs contain a conserved region of sequence at the NH 2 terminus that is required and sufficient for the inhibition of cyclin/Cdk complexes, whereas the COOH terminal regions are variable in length and function ( 12, 14 - 16 ). (aacrjournals.org)
  • Importantly, PIK5-12d was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. (bvsalud.org)
  • The inhibition of mitochondrial activity by various pharmacological inhibitors, as well as by gene-specific targeting using siRNA-mediated technology showed a dramatic attenuation of polyploidy and bi-nucleation development during in vitro stromal cell decidualization, suggesting mitochondria play a major role in positive regulation of decidual cell polyploidization. (plos.org)
  • Although one molecule of p21 is sufficient to inhibit cyclin/Cdk complexes ( 22 ), Cip/Kip CKIs have been detected in active cyclin D/Cdk4 complexes ( 24 - 27 ). (aacrjournals.org)
  • p21 was shown to stabilize interactions between Cdk4 and cyclin D and promote the formation of active complexes in a concentration-dependent manner ( 27 ). (aacrjournals.org)
  • [3] Mitogenic signals received throughout G1-phase cause gradual accumulation of cyclin D, which complexes with CDK4/6. (wikipedia.org)
  • [3] Active cyclin D-CDK4/6 complex induces release of E2F transcription factor, which in turn initiates expression of S-phase genes. (wikipedia.org)
  • Emerging evidence has shown that the F-box protein S-phase kinase associated protein 2 (Skp2) also plays an important role in the pathogenesis of breast cancer. (frontiersin.org)
  • S-phase kinase associated protein 2 belongs to ubiquitin-proteasome system (UPS) that plays vital roles in regulating many biological processes by controlling the timely turn-over of proteins ( Frescas and Pagano, 2008 ). (frontiersin.org)
  • [4] This process depends on the kinase activity of Cdc7 and various S-phase CDKs, both of which are upregulated upon S-phase entry. (wikipedia.org)
  • As a proliferation inhibitor, p21 is poised to play an important role in preventing tumor development. (aacrjournals.org)
  • Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. (bvsalud.org)