TP53 in cancer origin and treatment
J. K. Cowell in Molecular Genetics of Cancer, 2003
At variance with other tumor suppressor genes, cells with TP53 mutations typically maintain expression of the full-length protein. This may suggest that mutant TP53 genes can contribute actively to cancer progression through gain of function activity (Dittmer et al., 1993; Michalovitz et al., 1991). Indeed, overexpression of certain mutant TP53 genes in tp53-null cells resulted in enhancement of transformed features, increased plating efficiency in culture, increased tumorigenicity and invasiveness in vivo (Dittmer et al., 1993; Gloushankova et al., 1997; Hsiao et al., 1994; Lotem and Sachs, 1995; Sun et al., 1993; Wolf et al., 1984). In addition, some TP53 mutants are capable (i) to further increase genetic instability by abrogating the mitotic spindle checkpoint (Gualberto et al., 1998); (ii) to change differentiation status of cells (Kremenetskaya et al., 1997) and (iii) to interfere with TP53-independent apoptosis (Peled et al., 1996), thus increasing resistance to certain chemotherapeutic drugs (Blandino et al., 1999; Li et al., 1998).
Senescent Cells as Drivers of Age-Related Diseases
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
Progression through the cell cycle requires cells to pass cell cycle checkpoints, namely the G1-S transition, the S-phase checkpoint, the G2 to M transition, and the mitotic spindle checkpoint [26]. Replicative senescent cells become permanently arrested at G1 and G2 phases of the cell cycle [27,28]. Cellular senescence caused by telomere erosion evokes a DNA damage response (DDR), prompting the persistent activation of p53 via the ataxia telangiectasia mutated (ATM)/ATR DNA damage signaling pathway [29]. Upregulation of p21, a downstream effector of p53, is necessary to induce G1 cell cycle arrest following exposure to DNA-damaging agents [30]. Aside from triggering proliferative arrest in G1, p21 may also induce permanent G2 arrest in a number of senescent cells [31]. In contrast, loss of p21 causes DNA damaged cells to go through additional S-phases, resulting in polyploidy and subsequent apoptosis [32].
The Anticancer Potential of the Bacterial Protein Azurin and Its Derived Peptide p28
Ananda M. Chakrabarty, Arsénio M. Fialho in Microbial Infections and Cancer Therapy, 2019
Nowadays, chemotherapy includes DNA-damaging and antimitotic agents. DNA-damaging agents intercalate with DNA, inducing double strand breaks that induce ataxia-telangiectasia mutated (ATM)-dependent nuclear accumulation of p53 [57]. In addition, the apoptotic pathway via Bcl-2/Bax and the caspase cascade, as well as the necrotic pathway through toll-like receptors are targets for DNA-damaging agents [58]. On the other hand, antimitotic agents bind to the β-tubulin subunits of microtubules. This interaction leads to prolonged activation of the mitotic spindle checkpoint and mitotic arrest, followed by mitotic slippage and induction of apoptosis. These agents, also called taxanes, still induce post-transcriptional acetylation and phosphorylation of p53, which leads to its intracellular increase, upregulation of p21 protein, and inhibition of the cell cycle and also leads to apoptosis [59].
Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I
Published in Expert Opinion on Drug Delivery, 2021
Archana Upadhya, Khushwant S. Yadav, Ambikanandan Misra
The taxanes (paclitaxel and docetaxel) inhibit depolymerization of microtubules thus changing microtubule dynamics and eventually causing cell death by blocking cellular mitosis [115]. The factors for resistance to taxane-based therapy are increased expression of class III tubulin [116] and its mutations, up-regulation of histone deacetylase 6 (HDAC 6) and impairment of the mitotic spindle checkpoint [111]. The function of the mitotic spindle checkpoint is to block the segregation of abnormal chromosomes. In lung cancer cells, the mitotic spindle checkpoint is dysregulated [79,111]. The taxanes bind specifically to class I β tubulin isoform which differs in critical binding residues from the class III β isoform [117]. Class III β – tubulin is one of the β isoforms that heterodimerize with α subunits to form microtubules essential for cell division [117] and its high expression correlates with poor survival in NSCLC [118]. Histone acetylation and deacetylation regulate transcription of DNA segments. Histone acetylases (HATs) promote transcription while histone deacetylases (HDACs) inhibit transcription by making DNA inaccessible. Histone deacetylase six interacts with histone and non-histone substrates. Non – histone interactors are α-tubulin, contractin and heat shock protein 90 (Hsp90) which when modified by HDAC6 can promote cell proliferation, metastasis, invasion, and mitosis [119].
Further insights into testicular germ cell tumor oncogenesis: potential therapeutic targets
Published in Expert Review of Anticancer Therapy, 2020
Paolo Chieffi, Marco De Martino, Francesco Esposito
This kinase phosphorylates the H3 histone at serine 10, regulating chromosome condensation, alignment, and segregation. Also, spindle checkpoint function and cytokinesis are controlled by Aurora B kinase [54]. Furthermore, centrosome amplification has been connected to aneuploidy of TGCTs as reported by several research works [54]. Notably, in GC1 and TCam-2 testis-derived cell lines, the cell growth rate is strongly reduced following the inhibition of Aurora B kinase activity [55]. Definitely, AZD1152, ZM447439, Hesperadin 8, and VX-680 are Aurora B inhibitors that have been tested [55,56]. In particular, AZD1152 was tested in an extensive panel of human cancer xenograft considerably preventing the growth of tumors. Importantly, AZD1152 and other Aurora B inhibitors (ZM2, ZM3, GSK1070916) which block the phosphorylation of H3 histone on serine 10 [56], then abolishing cell division, show a reversible neutropenia as a main side effect, and they are in early clinical evaluation [55].
Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
The mitotic spindle checkpoint begins when all the chromosomes have been aligned appropriately at the mitotic plate under bipolar tension. This checkpoint ensures proper chromatid attachment prior to progression from metaphase to anaphase, which is sensed by APC-cdc20 that initiates the process to promote ubiquitin-mediated degradation of multiple substrates [18].
Related Knowledge Centers
- Cell Cycle Checkpoint
- Chromatid
- Kinetochore
- Spindle Apparatus
- Meiosis
- Metaphase
- Mitosis
- Chromosome
- Cell
- Anaphase-Promoting Complex