Hedgehog signaling drives medulloblastoma growth via CDK6

Raleigh, David R.; Choksi, Pervinder K.; Krup, Alexis Leigh; Wasima, Mayer; Santos, Nicole; Reiter, Jeremy F.

doi:10.1172/jci92710

Cited by 49 publications

(45 citation statements)

References 25 publications

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“…An alternative pharmacologic target of oncogenic HH signaling in medulloblastoma is cyclin-dependent kinase 6 (CDK6), a mitogenic kinase and direct transcriptional target of GLI2 ( Figure 3 and refs. 90,91). When activated through interaction with cyclin D1, CDK6 induces cell cycle progression by phosphorylating the tumor suppressor RB and relieving repression of E2F transcription factors.…”

Section: Number 2 February 2019mentioning

confidence: 99%

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

Raleigh¹,

Reiter²

2019

Journal of Clinical Investigation

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Section: Number 2 February 2019mentioning

confidence: 99%

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

Raleigh¹,

Reiter²

2019

Journal of Clinical Investigation

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“…We provided evidence that ciliary HH signaling in the intestinal mesenchyme patterns the circumferential smooth muscle to promote growth. The role of HH signaling in intestinal growth is therefore distinct from its roles in tissues such as the cerebellum and skin, where it directly induces the expression of drivers of the cell cycle (Lopez-Rios et al, 2012;Raleigh et al, 2018). Instead, the intestine represents a distinct model of how HH signaling functions in organ development: HH signaling patterns the gut, and this patterning, acting via mechanical influences interpreted by the Hippo pathway, promotes proliferation.…”

Section: Discussionmentioning

confidence: 99%

Ciliary signaling-patterned smooth muscle drives tubular elongation

Yang

Päivinen

Xie

et al. 2020

Preprint

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SummaryDuring development, many tubular organs undergo extensive longitudinal growth to reach their defined length, essential for their function, but how they lengthen is poorly understood. Here, we found that primary cilia are critical for the elongation of the small intestine and esophagus during murine embryonic development. More specifically, HH ligands produced by the epithelium signaled via cilia in the surrounding mesenchyme to pattern the smooth muscle. Like attenuated ciliary HH signaling, partial ablation of the smooth muscle reduced elongation, revealing an essential role for smooth muscle in longitudinal growth. Disruption of cilia, HH signaling or the smooth muscle reduced residual stress within the gut wall, indicating that smooth muscle contributes to the mechanical properties of the developing gut. Reducing residual stress decreased nuclear YAP, an effector of the mechanotransductive Hippo pathway. Removing YAP in the mesenchyme did not affect smooth muscle formation, but attenuated proliferation and elongation, demonstrating that YAP interprets smooth muscle-generated force to promote proliferation. Together, our results reveal that ciliary signaling directs the formation of the smooth muscle layer which, in turn, generates mechanical forces that activate YAP-mediated proliferation. As this interplay of biochemical and mechanical signals drives elongation of both the esophagus and small intestine, we propose that this mechanism may underlie tubular organ elongation generally.HighlightsPrimary cilia are essential for the elongation of the small intestine and esophagus during embryonic developmentCiliary signaling patterns the smooth muscle in the developing intestine and esophagusThe smooth muscle contributes to tissue mechanicsSmooth muscle-generated strain activates YAP to drive longitudinal growth of the tubular organs

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“…Wang et al confirmed that the increased expression of CDK6 was synchronous with the development of BC, indicating that it could be considered a prognostic biomarker for patients with BC [20] . In addition, abnormal CDK6 expression has also been detected in breast cancer [21] , pancreatic cancer [22] , malignant glioma [23] , and medulloblastoma [24] . Activation of cyclin E/CDK2 and cyclin D1/CDK4 in cell cycle progression could contribute to urothelial proliferation [25] , and down-regulation of CDK2 in BC was first reported in this study.…”

Section: Discussionmentioning

confidence: 99%

The NRP1 gene regulates proliferation, apoptosis, migration, and invasion in T24 and 5637 bladder cancer cells

Han

Dong

Hao

et al. 2020

Preprint

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Background Bladder urothelial carcinoma (BC) is a fatal invasive malignancy and the most common malignancy of the urinary system. In the current study, we investigate the function and mechanisms of Neuropilin-1 (NRP1), the co-receptor for vascular endothelial growth factor, in BC pathogenesis and progression. Methods The expression of NRP1 was assessed in several BC cell lines. Additionally, the biological function of NRP1 in proliferation, apoptosis, angiogenesis, migration, and invasion of BC were validated in vitro by silencing NRP1. Moreover, gene expression profiling chip analysis was conducted, and the related signalling pathways were confirmed by Western blot to reveal the potential molecular mechanisms by which NRP1 promotes the malignant progression of BC. Results Overexpression of NRP1 was observed in several human BC cell lines. NRP1 knockdown inhibited cell proliferation, promoted apoptosis, and decreased angiogenesis, migration, and invasion in T24 and 5637 human BC cells. Microarray analysis results indicated that the expression of NRP1 was correlated with the levels of cyclin dependent kinase (CDK) 4, baculoviral IAP repeat containing 3, Cyclin E 2, CDK2, and AP-1 transcription factor subunit in BC. We also demonstrated that the biological function of NRP1was associated with activation of the mitogen-activated protein kinase (MAPK) signalling pathway. Conclusions Our findings provide evidence that NRP1, as a potential tumour promoter, contributes to the metastasis and invasion of BC, which is associated with the activation of the MAPK pathway. Targeting NRP1 has the potential to become a new therapeutic strategy to benefit more patients with BC or other cancers.

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Hedgehog signaling drives medulloblastoma growth via CDK6

Cited by 49 publications

References 25 publications

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

Ciliary signaling-patterned smooth muscle drives tubular elongation

The NRP1 gene regulates proliferation, apoptosis, migration, and invasion in T24 and 5637 bladder cancer cells

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