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Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Persistent pathway activation may occur through the preexisting loss of the negative regulators of RAS/MAPK signaling, such as loss of neurofibromatosis type 1 (NF1), RAC1 gain of function mutations, COT amplification (Proto-Oncogene C-Cot or Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8)) [6, 60, 61]. RAF pathway blockade can be bypassed through a number of downstream mechanisms, including preexisting copy number amplification of cyclin D1 (CCND1), which is found in 15–20% of BRAF-mutant melanomas [62]. In preclinical models, resistance-induced cyclin D1 overexpression was enhanced when cyclin D1 and CDK4 were concurrently overexpressed [62]. Elevated expression of the transcription factor YAP1 also was associated with resistance to BRAF inhibitor treatment in preclinical models and with poor survival in patients with melanoma and NSCLC treated with BRAF inhibitors [63, 64]. In preclinical models, resistance to BRAF inhibition was reversed by genetic inhibition of YAP. Alternate pathways may be activated to bypass BRAF/MEK blockade. For example, loss offunction of the tumor suppressor phosphatase and tensin homolog (PTEN) gene correlates with poor prognosis with BRAF inhibitor treatment through activation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway and suppression of expression of the proapoptotic protein, BIM [65, 66].
Mechanotransduction Mechanisms of Hypertrophy and Performance with Resistance Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Andrew C. Fry, Justin X. Nicoll, Luke A. Olsen
The recruitment of mTORC1 to the lysosome may influence its activity through other mechanisms than those mentioned previously; specifically, through the lipid second messenger phosphatidic acid (PA). PA can directly activate mTORC1 through binding to its FKBP12-binding domain (184). Interestingly, phosphatidic acid increases following exercise and accumulates through the mechanosensitive properties of its upstream enzyme diacylglycerol kinase zeta (DGKζ) and phospholipase D (PLD). Indeed, the inhibition of these two enzymes attenuated mechanically driven muscle growth, while the overexpression of either PLD or DGKζ resulted in muscle hypertrophy. Moreover, PA localizes around the lysosome rendering it in close proximity to mTORC1. Outside of its ability to interact with mTORC1, PA also mediates the activity of the energy-sensing HIPPO pathway via indirect activation of yes-associated protein (YAP) through inhibition of its downstream inhibitor, long-acting thyroid stimulator (LATS) (65). Following this physical activity–induced decrease in YAP inhibition, YAP can then translocate to the nucleus, directly regulating the expression of hypertrophic genes.
Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
Patterns of gene expression were used to define three sub-groups, then subsequently nine.243 Supratentorial tumors, for example, express NOTCH and EPHB-EPHRIN pathways, whereas spinal ependymomas express members of the Homeobox (HOX) family. Particular importance is attached to expression of fusion genes involving REL-A and YAP-1.
The yes-associated protein (YAP) is associated with resistance to anti-GD2 immunotherapy in neuroblastoma through downregulation of ST8SIA1
Published in OncoImmunology, 2023
Adeiye A. Pilgrim, Hunter C. Jonus, Andrew Ho, Anna C. Cole, Jenny Shim, Kelly C. Goldsmith
YAP is a transcriptional co-regulator that primarily binds to TEAD family transcription factors.11,12 YAP and TEAD transcriptionally activate or repress downstream target genes, contributing to cell proliferation, self-renewal and survival in many cancers, including neuroblastoma.13,14 YAP is highly expressed in neuroblastoma cells that demonstrate an undifferentiated mesenchymal phenotype, which is characteristically chemotherapy resistant.10,15 Using paired high-risk neuroblastoma tumors derived from the same patient at diagnosis and at tumor recurrence following chemotherapy, we have previously shown increased YAP expression and transcriptional activity at relapse.16 Genetic inhibition of YAP delayed tumor growth and sensitized NRAS-mutated neuroblastoma xenografts to cytotoxic chemotherapy and MEK inhibitor treatment in vivo, yet failed to have the same effects in vitro, suggesting YAP plays a crucial role driving therapy resistance within the solid tumor microenvironment (TME).16,17 RNA sequencing of neuroblastomas with and without YAP genetic knockdown revealed that YAP suppresses the BH3 pro-death gene, HRK, to attenuate chemotherapy and MEK inhibitor responses in vivo. 16 Therefore, YAP upregulation following chemotherapy and relapse promotes therapy resistance in high-risk neuroblastoma through transcriptional repression of genes that play a role in the TME.
Yap Expression Is Closely Related to Tumor Angiogenesis and Poor Prognosis in Hepatoblastoma
Published in Fetal and Pediatric Pathology, 2022
Wenchen Gong, Zhiqiang Han, Feng Fang, Lu Chen
The YAP protein is a crucial transcriptional coactivator protein that is downstream of Hippo signaling and the WNT/β-catenin pathway [21,22]. It executes functions such as promoting tissue regeneration, and maintaining stem cell self-renewal and repair [23–25]. Given the critical role of YAP in cell proliferation, apoptosis regulation and tumor formation have gradually been revealed to be related to YAP, and studies on YAP have increased. Previous findings indicated that YAP is highly expressed in many malignant tumors and promotes the invasion and metastasis of tumor cells [11–17]. YAP represents an independent prognostic marker in hepatocellular carcinoma, and p-YAP dephosphorylation results in nuclear localization, where YAP regulates the malignant biological behavior of tumors [26,27]. Recent studies reported that Wnt/β-catenin collaborated with YAP signaling to induce hepatoblastoma formation and development in the mouse liver [28–30], whereas it had been well known that aberrant β-catenin expression was associated with hepatoblastoma pathogenesis [31–34]. Supportively, the present study demonstrated that overexpression of YAP was significantly correlated with the malignant biological behavior of hepatoblastoma. The limitation of this study is the relatively small number of cases, and we hope that additional study will be performed in multiple centers with more cases.
De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia
Published in Ophthalmic Genetics, 2022
Charles DeYoung, Bin Guan, Ehsan Ullah, Delphine Blain, Robert B. Hufnagel, Brian P. Brooks
YAP1 (OMIM 606608) encodes Yes-associated protein 1, a known effector of the Hippo-signaling pathway, and is implicated in the development of several organs, including the eye (1). YAP1 activation is also known to play a role in the initiation, progression, and metastasis of multiple cancers and is being investigated as a potential target for cancer treatment (2). In situ hybridization of human embryonic tissue has detected YAP1 expression in the developing human eye, neural tube, brain, and kidney (3). YAP1 mutations have previously been linked to coloboma, which is characterized by the congenital loss of normal tissue in or around the eye (4). The resulting defects can cause a range of visual dysfunctions, depending on the size and location of the coloboma. Here, we present a one-year-old male infant with bilateral uveal colobomata and microphthalmia in the right eye, with a de novo YAP1 frameshift mutation.