What Is The Role Of Cyclins In A Cell – Combination of sorafenib and betulinic acid synergistically induces cell cycle arrest and inhibits clonogenic activity in pancreatic ductal adenocarcinoma cells
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What Is The Role Of Cyclins In A Cell
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Cell Cycle Regulators (article)
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Cyclin Dependent Kinase
By Balbina García-Reyes Balbina García-Reyes Scilit Preprints.org Google Scholar 1, †, Anna-Laura Kretz Anna-Laura Kretz Scilit Preprints.org Google Scholar 1, †, Jan-Philipp Ruff Jan-Philipp Ruff Scilit Preprints.org Google Scholar 1, Silvia Von Karstedt Silvia Von Karstedt Scilit Preprints.org Google Scholar 2, 3, Andreas Hillenbrand Andreas Hillenbrand Scilit Preprints.org Google Scholar 1, Uwe Knippschild Uwe Knippschild Scilit Preprints.org Google Scholar 1, Doris Henne-Bruns Doris Henne- Bruns Scilit Preprints.org Google Scholar 1 and Johannes Lemke Johannes Lemke Scilit Preprints.org Google Scholar 1, *
Cologne Excellence Cluster on Cellular Stress Responses in Age-Related Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany.
Received date: August 31, 2018 / Revision date: September 27, 2018 / Acceptance date: October 11, 2018 / Publication date: October 18, 2018
The cyclin-dependent kinase (CDK) family has important functions in cell cycle regulation and transcriptional elongation control. Furthermore, dysregulation of CDKs is thought to be associated with Cancer development and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer treatment. This idea is of particular interest in combating pancreatic ductal adenocarcinoma (PDAC), a cancer with a dismal prognosis primarily due to PDAC’s resistance to conventional treatments. Here, we review current knowledge about CDK biology, the role of CDKs in cancer, and the potential of CDK-targeted therapies as novel therapeutic strategies for PDAC.
Surprising Regulation Of Cell Cycle Entry
Despite advances in diagnosis and treatment, exocrine pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), remains a major challenge for oncology. PDAC is one of two cancers in which survival rates have not made substantial progress over the past few decades, the second being lung cancer [1]. Because pancreatic cancer presents with nonspecific symptoms such as diffuse abdominal discomfort and anorexia [2], it is often diagnosed only at a later stage when it is more difficult to treat [3].
Pancreatic cancer has an incidence of 4.2 per 100,000 people, making it the 12th most common cancer in humans [4]. Among gastrointestinal malignancies, PDAC ranks second after colorectal cancer as the most commonly occurring cancer [ 1 , 5 ]. PDAC is one of the most lethal cancers, with a cumulative 5-year survival rate of only 8% [1, 3]. This poor survival rate is partly due to late diagnosis, as suggested by the fact that when only localized tumor without metastases is present, survival is 4-fold improved at 28%. [1]. Pancreatic cancer ranks fourth in cancer-related mortality statistics for both men and women [1]. Pancreatic cancer most commonly occurs in people in their 70s and 80s, but less frequently it has also been reported in people under 40, making pancreatic cancer an age-related cancer. It is [6].
The only potential treatment for PDAC is surgical resection [2, 7, 8]. However, this possibility is hampered by the aggressive nature of the disease, which exhibits early spread, invasion, distant metastases, and typical resistance to conventional radiotherapy and chemotherapy [2, 3, 9, 10, 11]. At the time of diagnosis, only 15-20% of pancreatic cancers are operable (that is, they have not spread to other organs), while the remainder can only be treated with palliative chemotherapy, often with unfavorable outcomes. obtained [12]. Most patients treated with curative intent develop in situ recurrence and distant metastases [2, 13]. Therefore, clinicians need appropriate and effective chemotherapy regimens. Adjuvant treatment is mainly based on gemcitabine. Palliative disease is mainly treated with gemcitabine or FOLFIRINOX (FOL = folinic acid = leucovorin, F = 5-FU = 5-fluorouracil, IRIN = irinotecan, OX = oxaliplatin) or the tyrosine kinase inhibitor erlotinib [14, 15] .
The prodrug gemcitabine has long been the gold standard for adjuvant therapy. However, the effect on improving median survival is at best modest [16, 17]. Paclitaxel, currently prepared as nab-paclitaxel (nanoparticle albumin binding), improved the treatment success rate when combined with gemcitabine, although to a less than satisfactory level [18, 19, 20]. FOLFIRINOX has become a second-line therapy for advanced and metastatic pancreatic cancer since its introduction as a PDAC treatment several years ago [21, 22]. However, emerging trends [23] indicate that FOLFIRINOX is superior to gemcitabine due to significantly better overall survival, disease-free survival, and metastasis-free survival, and is therefore superior to gemcitabine in treatment and adjuvant therapy. This indicates its role as a first-line drug. in randomized clinical trials [24, 25].
A New Linear Cyclin Docking Motif That Mediates Exclusively S‐phase Cdk‐specific Signaling
Unfortunately, gemcitabine, nab-paclitaxel, and forfirinox are highly toxic [13, 20, 26, 27]. Furthermore, currently approved treatments for PDAC do not yield satisfactory results. Therefore, new therapeutic strategies with reduced toxicity and higher on-target efficacy are needed. Cyclin-dependent kinases (CDKs) have been proposed as potential targets for pharmacological inhibition against several cancer entities. Indeed, there are several successful examples of CDK inhibition in clinical settings, particularly against breast cancer, non-small cell lung cancer, melanoma, and squamous cell carcinoma of the head and neck (reviewed in [28]). In the case of pancreatic cancer, CDKs play an important role in the pathobiology of this disease, but available clinical and preclinical evidence regarding the benefits of CDK inhibition is still lacking.
Cyclin-dependent kinases (CDKs) are serine/threonine kinases that control cell cycle progression and other important functions within the cell. Based on the homology of their catalytic domains, CDKs are classified into mitogen-activated protein kinases (MAPKs), glycogen synthase kinase 3β (Gsk3β), members of the dual-specificity tyrosine-regulated kinase (DYRK) family, and similar members of CDKs. The kinase belongs to the CMGC group of kinases (named after the members’ initials) [29, 30]. CDKs are activated by cyclins and function as regulatory subunits. These CDK/cyclin complexes are fundamental to the orderly progression of cells [31]. Studies examining the function of CDKs and cyclins have revealed that, in fact, these proteins have other related roles beyond cell cycle regulation [31, 32]. These other roles include, for example, transcriptional regulation, epigenetic regulation, metabolism, stem cell regeneration, and spermatogenesis [33, 34, 35, 36].
According to the classification of Malumbres et al. [37], there are 21 CDKs (see Table 1), which contain an ATP-binding pocket, the amino acid sequence PSTAIRE as a cyclin-binding domain, and a conserved catalytic domain containing an activating T-loop motif. are sharing. Activated CDK/cyclin complexes depend on phosphorylation of the T-loop of the respective CDK. Cyclins interact with the PSTAIRE helix, displacing the T-loop and exposing the substrate-binding domain of the kinase, thereby allowing its phosphorylation. Unlike CDKs, cyclins are heterogeneous proteins characterized by the presence of so-called cyclin boxes that mediate binding to CDKs [38]. Outside this domain, their arrangement is highly diverse. Most known cyclins promote CDK activity. Several regulatory mechanisms exist, including those regulating CDKs at the posttranscriptional level, CDK inhibitors exerting negative regulation, phosphorylation status, protein folding, and subcellular localization [ 39 , 40 , 41]. Phosphorylation can regulate CDKs in both negative and positive ways [42]. For example, CDK1 has inhibitory (CDK1 threonine 14, T14; tyrosine 15, Y15) and stimulatory (CDK1 threonine 161, T161) phosphorylation sites [43, 44]. Phosphorylation of T14 and Y15 within the ATP binding site by the inhibitory kinases Wee1 and Myt1 prevents proper ATP alignment, whereas T-loop phosphorylation of T161 by CDK-activated kinases (CAKs) inhibits substrate binding and complex stability. improves CDK activation and allows complete CDK activation. 42]. This review provides an overview of the role of CDKs in the cell cycle and transcription.
The cell cycle is one of the most essential and evolutionarily conserved cellular processes. CDKs and cyclins are the main proteins driving it [93, 94, 95]. Typically, these protein families function as heterodimers that control different stages of the cell cycle as CDK/cyclin complexes (Figure 1). CDKs that are not bound to cyclins are normally inactive, but become activated when they form a complex with a cyclin partner.
When Cyclin‐dependent Kinases Meet Viral Infections, Including Sars‐cov‐2
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