The <scp>LIN28B</scp>–let‐7–<scp>PBK</scp> pathway is essential for group 3 medulloblastoma tumor growth and survival

Shahab, Shubin W.; Roggeveen, Christianna M.; Sun, Jiarong; Kunhiraman, Haritha; McSwain, Leon F.; Juraschka, Kyle; Kumar, Sachin A.; Saulnier, Olivier; Taylor, Michael D.; Schniederjan, Matthew; Schnepp, Robert W.; MacDonald, Tobey J; Kenney, Anna Marie

doi:10.1002/1878-0261.13477

Cited by 5 publications

(2 citation statements)

References 57 publications

(80 reference statements)

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“…Through consulting the literature, we were particularly interested in PBK, which is overexpressed in several human malignancies. [20][21][22][23][24] By analyzing the amino acid sequence of PBK, we found that PBK at Thr9 may be the potential phosphorylation site of CDK5. To further verify that CDK5 phosphorylates PBK-T9, HEK293 cells were transfected with GFP-CDK5 and FLAG-PBK.…”

Section: Phosphorylation Of Pbk At Thr9 By Cdk5 Promotes Cell Prolife...mentioning

confidence: 99%

Phosphorylation of PBK at Thr9 by CDK5 correlates with invasion of prolactinomas

Fang,

Liu,

Nie

et al. 2024

CNS Neurosci Ther

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ContextProlactinomas are the most prevalent functional pituitary neuroendocrine tumors (PitNETs), and they are invasive to surrounding anatomic structures. The detailed mechanisms of invasion are not yet clear.ObjectiveWe explored the role of PBK phosphorylation in the proliferation and invasion of prolactinomas and its possible mechanism.ResultsWe report that PBK directly binds to and is phosphorylated at Thr9 by cyclin‐dependent kinase 5 (CDK5), which promotes GH3 cell EMT progression and proliferation. Phosphorylation of PBK at Thr9 (pPBK‐T9) by CDK5 enhances the stability of PBK. p38 is one of the downstream targets of PBK, and its phosphorylation is reduced as pPBK‐T9 increases in vivo and in vitro. Furthermore, we found that pPBK‐T9 is highly expressed in invasive PitNETs and was significantly correlated with invasion by univariate and multivariate analyses.ConclusionsPhosphorylation of PBK at Thr9 by CDK5 promotes cell proliferation and EMT progression in prolactinomas.

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Section: Phosphorylation Of Pbk At Thr9 By Cdk5 Promotes Cell Prolife...mentioning

confidence: 99%

Phosphorylation of PBK at Thr9 by CDK5 correlates with invasion of prolactinomas

Fang,

Liu,

Nie

et al. 2024

CNS Neurosci Ther

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“…Like DNA-binding proteins, small-molecule inhibition of RBPs is difficult, although recent high-throughput approaches have generated candidates ( Wu, 2020 ). The most promising LIN28(A/B) inhibitor is C1632, which targets LIN28B + cell lines both by disruption of LIN28B–let-7 interaction ( Franses et al, 2020 ; Zhang Q. et al, 2023 ; Shahab et al, 2023 ) and in Ewing sarcoma by disruption of the interaction between EWS-FLI1 mRNA and LIN28B ( Keskin et al, 2020 ). Other molecules such as LI71 bind the cold shock domain and have efficacy against LIN28B + cancer cell lines ( Wang L. et al, 2018 ).…”

Section: Targeting Aberrant Stem Cell Programs In Leukemia For Therapymentioning

confidence: 99%

Aberrant stem cell and developmental programs in pediatric leukemia

Ling,

Cross,

Roy

2024

Front. Cell Dev. Biol.

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Hematopoiesis is a finely orchestrated process, whereby hematopoietic stem cells give rise to all mature blood cells. Crucially, they maintain the ability to self-renew and/or differentiate to replenish downstream progeny. This process starts at an embryonic stage and continues throughout the human lifespan. Blood cancers such as leukemia occur when normal hematopoiesis is disrupted, leading to uncontrolled proliferation and a block in differentiation of progenitors of a particular lineage (myeloid or lymphoid). Although normal stem cell programs are crucial for tissue homeostasis, these can be co-opted in many cancers, including leukemia. Myeloid or lymphoid leukemias often display stem cell-like properties that not only allow proliferation and survival of leukemic blasts but also enable them to escape treatments currently employed to treat patients. In addition, some leukemias, especially in children, have a fetal stem cell profile, which may reflect the developmental origins of the disease. Aberrant fetal stem cell programs necessary for leukemia maintenance are particularly attractive therapeutic targets. Understanding how hijacked stem cell programs lead to aberrant gene expression in place and time, and drive the biology of leukemia, will help us develop the best treatment strategies for patients.

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The RAS oncogene in brain tumors and the involvement of let-7 microRNA

Messina

2024

Mol Biol Rep

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RAS oncogenes are master regulator genes in many cancers. In general, RAS-driven cancers have an oncogenic RAS mutation that promotes disease progression (colon, lung, pancreas). In contrast, brain tumors are not necessarily RAS-driven cancers because RAS mutations are rarely observed. In particular, glioblastomas (the most lethal brain tumor) do not appear to have dominant genetic mutations that are suitable for targeted therapy. Standard treatment for most brain tumors continues to focus on maximal surgical resection, radiotherapy and chemotherapy. Yet the convergence of genomic aberrations such as EGFR, PDGFR and NF1 (some of which are clinically effective) with activation of the RAS/MAPK cascade is still considered a key point in gliomagenesis, and KRAS is undoubtedly a driving gene in gliomagenesis in mice. In cancer, microRNAs (miRNA) are small, non-coding RNAs that regulate carcinogenesis. However, the functional consequences of aberrant miRNA expression in cancer are still poorly understood. let-7 encodes an intergenic miRNA that is classified as a tumour suppressor, at least in lung cancer. Let-7 suppresses a plethora of oncogenes such as RAS, HMGA, c-Myc, cyclin-D and thus suppresses cancer development, differentiation and progression. let-7 family members are direct regulators of certain RAS family genes by binding to the sequences in their 3′untranslated region (3′UTR). let-7 miRNA is involved in the malignant behaviour in vitro—proliferation, migration and invasion—of gliomas and stem-like glioma cells as well as in vivo models of glioblastoma multiforme (GBM) via KRAS inhibition. It also increases resistance to certain chemotherapeutic agents and radiotherapy in GBM. Although let-7 therapy is not yet established, this review updates the current state of knowledge on the contribution of miRNA let-7 in interaction with KRAS to the oncogenesis of brain tumours.

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The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival

Cited by 5 publications

References 57 publications

Phosphorylation of PBK at Thr9 by CDK5 correlates with invasion of prolactinomas

Phosphorylation of PBK at Thr9 by CDK5 correlates with invasion of prolactinomas

Aberrant stem cell and developmental programs in pediatric leukemia

The RAS oncogene in brain tumors and the involvement of let-7 microRNA

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