Tumour progression from established cancer cells also appears to depend on Ki-67. In early studies, the delivery of antisense oligonucleotides against Ki-67 in vivo was found to inhibit the establishment of tumours but not growth from existing tumours. This was reported for both syngeneic models of murine cancers (Kausch et al., 2003) and for xenografts from human renal carcinoma (Kausch et al., 2004, 2005). Interpretation of these studies requires caution because the downregulation of Ki-67 levels in tumours was not verified. In a subsequent study, despite only partial depletion of Ki-67 using shRNA, xenografts of human 786-0 renal cancer cell line showed a significant inhibition in growth (Zheng et al., 2009). A more recent study has found that tumours of DLD-1 colon cancer cells lacking Ki-67 engrafted at intermediate density subcutaneously into mice grow more slowly than their control counterparts, although, confusingly, this is not observed at low or high cell density (Cidado et al., 2016). In the 4T1 mouse mammary carcinoma model, Ki-67 knockout has been found to strongly reduce tumour growth in two immunocompromised mouse models (athymic nude and NOD SCID), despite unaltered cell proliferation, apoptosis and DNA damage in vivo (Mrouj et al., 2021). Similarly, human breast adenocarcinoma MDA-MB-231 Ki-67-knockout xenografts in nude mice grow slower than controls, and apoptosis and fibrosis are increased, whereas necrosis is reduced (Mrouj et al., 2021). Tumour growth is also decreased in xenografts originating from HeLa S3 cells with stably knocked down Ki-67, and again, cell proliferation is not affected in vivo, but necrosis and apoptosis are increased (Mrouj et al., 2021). Last but not least, Ki-67 knockout almost completely eliminates metastasis in the 4T1 model (Mrouj et al., 2021).
Importantly, a phase-separation model of transcriptional control has been proposed, which would explain the formation, characteristics and function of superenhancers (Hnisz et al., 2017). Coactivators that are enriched within superenhancers (BRD4 and MED1) have been demonstrated to phase separate (Sabari et al., 2018). RNA polymerase II transcription factories have also been shown to form phase-separated condensates, mediated by the activation domains of transcription factors interacting with the Mediator complex (Boija et al., 2018). In this context, the intrinsically disordered nature of activation domains would explain how hundreds of divergent transcription factors can interact with a very limited number of coactivators, such as the Mediator complex or p300 (histone acetyltransferase p300) (Allen and Taatjes, 2015).
[PORTABLE] Liliana Model Set 143
Thereafter, Imogen demanded they treat Laudna's body with respect, asking Ashton to carry her rather than put her in the portable hole. She noticed the lightning marks on her arms were about an inch and a half longer than before, reaching just above her elbows. Imogen Sent to Captain Xandis to summon the skyship, and then to Lord Eshteross, telling him that they had Armand Treshi, but lost Laudna, and asking if he knew someone powerful enough to bring her back. Eshteross was sympathetic but not encouraging, telling them to bring Laudna to him.[62] 2ff7e9595c
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