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The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
During the cell cycle, there are various decision points to determine whether the cell should continue to the next phase or not. The restriction point, R, during the G1 phase frequently becomes abnormal in cancer cells. Also, surveillance mechanisms are in place, known as check points, which assess the integrity of the process and a delay will occur in the G2 phase if damage to DNA is detected. During this time, repair mechanisms can work to rectify the damage, or if the damage incurred is too great, the cell may commit suicide during apoptosis. If these checkpoints fail to operate properly, cancer can arise. The replication of malfunctioning cells, which lack the necessary mechanisms of quality control can lead to the development of a tumour because there is no mechanism in place to stop their uncontrolled division.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
In mammalian cells there is a point in late G1 after which the cell cycle proceeds to DNA synthesis without the requirement of the continued presence of mitogenic stimulation or despite the addition of certain inhibitors of mitogenesis. The molecular gate that constitutes the restriction point is believed to be underphosphorylated retinoblastoma protein (Rb). Mitogenic stimulation activates the transcription of cyclins and cyclin-dependent kinases (Cdks). Cyclins and Cdks form complexes which are then phosphorylated by a cyclin-activating kinase (CAK). Activated cyclin–Cdk complexes appear in mid G1 and are responsible for the phosphorylation of the tumor suppressor gene product, Rb. Hypophosphorylated Rb is normally bound to the transcription factor E2F, inhibiting transcriptional activity. Phosphorylation of Rb bycyclin–Cdk complexes is a key event prior to the G1 restriction point, resulting in the dissociation of Rb from E2F, allowing the transcription of genes required for progression through S phase and DNA synthesis. A number of inhibitors of mitogenesis appear to act by interfering with the signalling step(s) that precede the dissociation of inhibitory proteins from the E2F complex.
Oncogenes and tumor suppressor genes
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. Giordano, S. Corso, P. Conrotto
The entry of cells into the cell cycle from a quiescent state, and their progression through it, are very tightly controlled events. When a cell reaches a point, called the ‘restriction point’, in late Gl, it becomes irreversibly committed to enter the S phase. The passage through the restriction point is regulated by several proteins such as cyclins, cyclin-dependent kinases and the Rb family of proteins. Deregulation of these proteins can lead to inappropriate progression into the cell cycle.
Association of MTHFR 677C > T, 1298A > C and MTR 2756A > G Polymorphisms with Susceptibility to Childhood Retinoblastoma: A Systematic Review and Met-Analysis
Published in Fetal and Pediatric Pathology, 2021
Mohsen Gohari, Mansour Moghimi, Hossein Aarafi, Ahmad Shajari, Jamal Jafari-Nedooshan, Mohammad Hosein Lookzadeh, Seyed Reza Mirjalili, Hossein Neamatzadeh
Retinoblastoma (Rb), arising from the developing retinal neural cells, is the most common intraocular malignancy in children [1–3]. Retinoblastoma accounts for 3% of all childhood malignancies in developed countries [1]. Retinoblastoma is predominantly found in children less than 5 years (95%), with a median age of diagnosis of 24 months in children with unilateral disease and 9-12 months in children with bilateral disease [4,5]. The frequency of retinoblastoma is 1 in 14,000 to 18,000 live births per year. There are approximately 9,000 new cases every year worldwide [6]. The prognosis of retinoblastoma differs dramatically worldwide, with survival rates of more than 90% in developed countries to as low as 23% in Africa [7,8]. Retinoblastoma has long been considered as a paradigm of hereditary cancers [9,10]. Retinoblastoma development can be initiated by inactivation of both alleles of RB1, the first identified tumor suppressor gene [11]. The RB protein has a key function as an important gatekeeper in the G1 restriction point of the cell cycle [12]. Some retinoblastoma cases (40%) have a heritable predisposition caused by either an inherited familial RB1 mutation (familial heritable Rb) or a de novo germline RB1 mutations of both cellular copies of the RB1 in the same retinoblast in 60% of cases (sporadic or non-familial heritable Rb) [13]. Hereditary retinoblastoma cases have an elevated risk of osteosarcomas, soft tissue sarcomas and other mesenchymal tumors through their teenage years, melanomas and brain tumors through middle age and epithelial malignancies such as lung and bladder cancer into later life [14,15].
Abemaciclib, a third CDK 4/6 inhibitor for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
Published in Expert Review of Anticancer Therapy, 2021
Georges El Hachem, Andrea Gombos, Ahmad Awada
A major hallmark of cancer cells survival is to evade extracellular and intracellular signals that are blocking proliferation [8,9]. The retinoblastoma (RB)-associated protein (tumor suppressor) is a major negative regulator of cell cycle progression. It is involved in determining whether a cell will proceed through the cycle of growth and division or enter a quiescent phase [10]. Regularly, the mammalian cell must pass the restriction point, called ‘’R,” a checkpoint essential to complete the cell cycle during the G1 phase [11]. Regulation of one or more proteins involved in this checkpoint is lost in many cancers. The activation of CDK4 and CDK6 by D-cyclins results in phosphorylation of the retinoblastoma-associated protein, thus allowing the cell to pass the “R” point and commit to division. When it is hyperphosphorylated, RB suppressive effect is inactivated leading to release of E2F family of transcription factors necessary for the progression of the cell cycle through the G1 to the S checkpoints [11]. Thus, CDK4 and 6 are involved in the promotion of cell cycle progression and their up-regulation is a major event for the proliferation and progression of breast cancer cells [11–13]. By inhibiting the CDK4/6, the cyclin D-CDK4/6 complex would not be able to phosphorylate RB. This prevents the cell from passing ''R'', and consequently from proceeding through the cell cycle. Figure 2 illustrates the mechanism of action of the CDK 4/6 inhibitors.
An analysis of available biomarker data for targeting cyclin-dependent kinases 4 and 6 (CDK4/6) in breast cancer
Published in Expert Review of Precision Medicine and Drug Development, 2019
Bruno Achutti Duso, Emanuela Ferraro, Luca Mazzarella, Camila Dagostim Jeremias, Giuseppe Curigliano
Estrogen receptor (ER)-positive disease (possibly all luminal breast cancers, including luminal androgen receptor [LAR]) almost always retains Rb function at presentation, theoretically providing an intact pathway upon which these agents abide. However, when the G1 restriction point is deregulated among this population, it consistently involve established alterations on genes coding for cyclin D1 (CCND1), p16INK4A (CDKN2A) and pRb (RB1), to name a few [26]. Even with a plethora of investigation over this topic, results do not seem to strictly follow the course from preclinical to clinial spheres and are for many times controversial. In the PALOMA-1/TRIO-18 trial first interim analysis, the presence of CCND1 amplification, loss of CDKN2A, or both did not correlate with different response rates [27]. PALOMA-2, likewise, did not find a correlation between expression levels of genes in the cyclin D-CDK4/6-Rb pathway through next-generation sequencing (NGS) and the significant benefit from the addition of a CDK4/6i [28].