The cell cycle and differentiation as integrated processes: Cyclins and CDKs reciprocally regulate Sox and Notch to balance stem cell maintenance

Muhr, Jonas; Hagey, Daniel W.

doi:10.1002/bies.202000285

Cited by 15 publications

(16 citation statements)

References 117 publications

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“…All relate to the cell cycle. Cell cycle dysregulation is a hallmark of tumor cells; cell cycle state regulates differentiation 47 . Signaling that promotes cell proliferation is expected to be stronger than that connected to differentiation.…”

Section: Resultsmentioning

confidence: 99%

Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

Yavuz,

Arici,

Demirel

et al. 2023

npj Genom. Med.

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Epidemiological studies suggest that individuals with neurodevelopmental disorders (NDDs) are more prone to develop certain types of cancer. Notably, however, the case statistics can be impacted by late discovery of cancer in individuals afflicted with NDDs, such as intellectual disorders, autism, and schizophrenia, which may bias the numbers. As to NDD-associated mutations, in most cases, they are germline while cancer mutations are sporadic, emerging during life. However, somatic mosaicism can spur NDDs, and cancer-related mutations can be germline. NDDs and cancer share proteins, pathways, and mutations. Here we ask (i) exactly which features they share, and (ii) how, despite their commonalities, they differ in clinical outcomes. To tackle these questions, we employed a statistical framework followed by network analysis. Our thorough exploration of the mutations, reconstructed disease-specific networks, pathways, and transcriptome levels and profiles of autism spectrum disorder (ASD) and cancers, point to signaling strength as the key factor: strong signaling promotes cell proliferation in cancer, and weaker (moderate) signaling impacts differentiation in ASD. Thus, we suggest that signaling strength, not activating mutations, can decide clinical outcome.

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Section: Resultsmentioning

confidence: 99%

Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

Yavuz,

Arici,

Demirel

et al. 2023

npj Genom. Med.

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“…There are many direct interactions between cell cycle regulators and the stemness pathway [ 45 , 46 ]. Therapies targeting tumor cell stemness should consider the impact on the cell cycle to more effectively suppress tumor cell proliferation and metastasis.…”

Section: Discussionmentioning

confidence: 99%

CDC45 promotes the stemness and metastasis in lung adenocarcinoma by affecting the cell cycle

Liu,

Han,

et al. 2024

J Transl Med

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Objective This study aimed to assess the functions of cell division cycle protein 45 (CDC45) in Non-small cell lung cancer (NSCLC) cancer and its effects on stemness and metastasis. Methods Firstly, differentially expressed genes related to lung cancer metastasis and stemness were screened by differential analysis and lasso regression. Then, in vitro, experiments such as colony formation assay, scratch assay, and transwell assay were conducted to evaluate the impact of CDC45 knockdown on the proliferation and migration abilities of lung cancer cells. Western blotting was used to measure the expression levels of related proteins and investigate the regulation of CDC45 on the cell cycle. Finally, in vivo model with subcutaneous injection of lung cancer cells was performed to verify the effect of CDC45 on tumor growth. Results This study identified CDC45 as a key gene potentially influencing tumor stemness and lymph node metastasis. Knockdown of CDC45 not only suppressed the proliferation and migration abilities of lung cancer cells but also caused cell cycle arrest at the G2/M phase. Further analysis revealed a negative correlation between CDC45 and cell cycle-related proteins, stemness-related markers, and tumor mutations. Mouse experiments confirmed that CDC45 knockdown inhibited tumor growth. Conclusion As a novel regulator of stemness, CDC45 plays a role in regulating lung cancer cell proliferation, migration, and cell cycle. Therefore, CDC45 may serve as a potential target for lung cancer treatment and provide a reference for further mechanistic research and therapeutic development.

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“…Bulk RNA-seq analysis shows that a few cell-cycle associated genes and biological pathways related to cell cycle regulation are up-regulated in PSCs isolated from Sfrp4 −/− mice, although PSC proliferation was not significantly affected by Sfrp4 deletion. Interactions between the cell cycle machinery and differentiation factors play a critical role in stem cell maintenance, proliferation, and differentiation ( 77 – 79 ). However, how the crosstalk between cell cycle proteins and growth factors affects stemness, proliferation, or lineage-restricted differentiation remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Sfrp4 is required to maintain Ctsk-lineage periosteal stem cell niche function

Chen,

Dong,

Raval

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling antagonistSfrp4is due in part to impaired periosteal apposition. The periosteum contains cells which function as a reservoir of stem cells and contribute to cortical bone expansion, homeostasis, and repair. However, the local or paracrine factors that govern stem cells within the periosteal niche remain elusive. Cathepsin K (Ctsk), together with additional stem cell surface markers, marks a subset of periosteal stem cells (PSCs) which possess self-renewal ability and inducible multipotency.Sfrp4is expressed in periosteal Ctsk-lineage cells, andSfrp4global deletion decreases the pool of PSCs, impairs their clonal multipotency for differentiation into osteoblasts and chondrocytes and formation of bone organoids. Bulk RNA sequencing analysis of Ctsk-lineage PSCs demonstrated thatSfrp4deletion down-regulates signaling pathways associated with skeletal development, positive regulation of bone mineralization, and wound healing. Supporting these findings,Sfrp4deletion hampers the periosteal response to bone injury and impairs Ctsk-lineage periosteal cell recruitment. Ctsk-lineage PSCs express the PTH receptor and PTH treatment increases the % of PSCs, a response not seen in the absence ofSfrp4. Importantly, in the absence ofSfrp4, PTH-dependent increase in cortical thickness and periosteal bone formation is markedly impaired. Thus, this study provides insights into the regulation of a specific population of periosteal cells by a secreted local factor, and shows a central role for Sfrp4 in the regulation of Ctsk-lineage periosteal stem cell differentiation and function.

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The cell cycle and differentiation as integrated processes: Cyclins and CDKs reciprocally regulate Sox and Notch to balance stem cell maintenance

Cited by 15 publications

References 117 publications

Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

CDC45 promotes the stemness and metastasis in lung adenocarcinoma by affecting the cell cycle

Sfrp4 is required to maintain Ctsk-lineage periosteal stem cell niche function

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