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The endometrium in polycystic ovary syndrome
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Recent studies have suggested endometrial progesterone resistance in women with PCOS (58,62–64), similar to that in women with endometriosis (65,66). Besides upregulated ER expression in secretory phase PCOS endometrium, downregulation of progesterone-related gene expression crucial for implantation and endometrial receptivity (αvβ3 integrin, claudin-4, and leukemia inhibitory factor [LIF]-1) has been observed in spontaneous or clomiphene citrate (CC)–induced secretory phase endometrium in women with PCOS (43,44,62). Furthermore, women with PCOS present with increased proliferation (upregulation of mitogen-inducible gene 6, cyclin B1, and cyclin E2) in CC- or progesterone-induced secretory phase endometrium, indicating blunted progesterone signaling (62). Recently, alterations in the PRα and β isoform ratio have been suggested to modulate steroid hormone action in human endometrium (63), although no in vivo data concerning humans, particularly women with PCOS, are available currently. In summary, in some women with PCOS, continuous estrogen exposure prevails, in both the proliferative and secretory phases, possibly impairing endometrial receptivity and leading in the term to hyperplasia and cancer (55). However, previous data and also some clinical observations reveal that not all women with PCOS have thickened endometrium or endometrial hyperplasia related to oligo-anovulation (56,57,67), and other mechanisms related to hyperandrogenism, genetic variations, glucose metabolism and hyperinsulinemia, or inflammation may underlie their endometrial abnormalities, predisposing to altered endometrial health (56,57). In all, the mechanisms described herein underscore the importance of interaction among different steroid hormone signaling pathways and balanced steroid receptor expression for normal endometrial development and function.
Screening and identification of key genes in imatinib-resistant chronic myelogenous leukemia cells: a bioinformatics study
Published in Hematology, 2021
Hong Zhang, Peiran Wang, Ting Song, Uwituze Laura Bonnette, Zhichao Zhang
CCNE2 (cyclin E2) regulates cell cycle progression by binding to cyclin dependent kinase 2 (CDK2) to form a serine/threonine kinase holoenzyme complex called CCNE2-CDK2 [37]. Aberrant regulation of CCNE2 is one of the biomarkers of tumorigenesis. CCNE2 overexpression has also been found in breast, ovarian, lung and other cancers [38–40]. In addition, CCNE2 were found to be highly expressed in hematologic malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL). Targeting peptides was found to kill leukemia cells by binding nonameric peptides of CCNE2 and inhibiting the expression of CCNE2 [41]. The overexpression of CCNE2 has been linked to high cellular proliferation, we suggest that overexpression of CCNE2 in K562 cells might show the highest resistance to the imatinib treatment. Moreover, a previous study has found that an indirubin derivative AGM130 induced apoptosis of imatinib-resistant CML cells by inhibited CCNE2-CDK2 activity [42].
Cyclin-dependent kinase inhibitors for the treatment of lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Angel Qin, Haritha G. Reddy, Frank D. Weinberg, Gregory P. Kalemkerian
CDK 2 plays a central role in the transition from G1 to S phase and CDK2 dysregulation has been implicated in carcinogenesis. CDK2 has a larger range of phosphorylation targets than CDK4/6, including proteins that control cell cycle progression, DNA replication, histone synthesis, and centrosome duplication [18,19]. CDK2 is activated through association with E- and A-type cyclins in late G1. Both RB and E2F regulate the expression of CDK2, cyclin E1 and cyclin E2 [20]. CDK 4/6 phosphorylation and subsequent inactivation of RB allows for CDK2 expression. Concomitantly, CDK2 activity reinforces the phosphorylation of additional sites on the RB protein allowing for irreversible initiation of S-phase-specific gene expression. CDK2 is also regulated by the CDK-interacting protein/kinase inhibitory protein (CIP/KIP) class of CDK inhibitors which bind to and inactivate the CDK2-cyclin complex [21]. Many cancers have low CIP/KIP family expression. For example, the CDK inhibitor p27KIP1 is down-regulated in a variety of tumor types allowing for deregulated progression through the cell cycle [22]. Similar to CDK4/6, CDK2 is also directly regulated by phosphorylation [23].
Interleukin-6 and tumour necrosis factor-α cooperatively promote cell cycle regulators and proliferate rheumatoid arthritis fibroblast-like synovial cells
Published in Scandinavian Journal of Rheumatology, 2019
K Kaneshiro, Y Sakai, K Suzuki, K Uchida, K Tateishi, Y Terashima, Y Kawasaki, N Shibanuma, K Yoshida, A Hashiramoto
In human embryonic kidney (HEK) 293 cells (JCRB9068, lot 10172008; NIBIOHN, Osaka, Japan), the expression of CDK6 mRNA was decreased by IL-6/sIL-6R, while expression of CDK4 mRNA, CYCLIN D, and pRB, and phosphorylation of pRB, were not modulated by IL-6/sIL-6R or TNF-α (Supplementary figure S2A and B). The mRNA expression of Cyclin E1 was increased by TNF-α and Cyclin E2 was decreased by IL-6/sIL-6R and TNF-α costimulation, while protein expression of CYCLIN E was changed by neither IL-6/sIL-6R nor TNF-α (Supplementary figure S2C). Finally, cell viability was decreased by TNF-α and costimulation by IL-6/sIL-6R and TNF-α, whereas it was not changed by sole IL-6/sIL-6R stimulation (Supplementary figure S2D). These results indicate that IL-6 and TNF-α may induce apoptosis but not proliferation of HEK293, unlike RA-FLS. Notably, major differences were seen in the expression of CDK6, Cyclin D, Cyclin E, and pRB (Figures 1, 2, 3, and 5, and Supplementary figure S2A–C).