DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway

Zhou, Yanyan; Huangfu, Shaohua; Li, Muxi; Tang, Chaohua; Qian, Jinjun; Guo, Mengjie; Zhou, Zuojian; Yang, Ye; Gu, Chunyan

doi:10.18632/aging.204326

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…17 Deleted in Azoospermia-Associated Protein 1 (DAZAP1) binds near the 3′ splice site, inducing exon 6 skipping and favouring the membrane-bound form. 169 The protein kinase C inducer, phorbol 12-myristate 13-acetate, and the calcium ionophore, A23187, facilitate the cleavage of transmembrane precursors, favouring soluble KITLG formation. 170 However, protein kinase C inhibition with calphostin C boosts the membrane-bound form.…”

Section: Intr Acellul Ar Reg Ul Ation Of K Itlgmentioning

confidence: 99%

“…Two KITLG isoforms result from tissue‐specific alternative splicing, producing distinct soluble‐to‐membrane‐bound KITLG mRNA ratios 17 . Deleted in Azoospermia‐Associated Protein 1 (DAZAP1) binds near the 3′ splice site, inducing exon 6 skipping and favouring the membrane‐bound form 169 . The protein kinase C inducer, phorbol 12‐myristate 13‐acetate, and the calcium ionophore, A23187, facilitate the cleavage of transmembrane precursors, favouring soluble KITLG formation 170 .…”

Section: Intracellular Regulation Of Kitlgmentioning

confidence: 99%

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Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases

Sevilla,

Grichnik

2024

Experimental Dermatology

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KIT ligand and its associated receptor KIT serve as a master regulatory system for both melanocytes and mast cells controlling survival, migration, proliferation and activation. Blockade of this pathway results in cell depletion, while overactivation leads to mastocytosis or melanoma. Expression defects are associated with pigmentary and mast cell disorders. KIT ligand regulation is complex but efficient targeting of this system would be of significant benefit to those suffering from melanocytic or mast cell disorders. Herein, we review the known associations of this pathway with cutaneous diseases and the regulators of this system both in skin and in the more well‐studied germ cell system. Exogenous agents modulating this pathway will also be presented. Ultimately, we will review potential therapeutic opportunities to help our patients with melanocytic and mast cell disease processes potentially including vitiligo, hair greying, melasma, urticaria, mastocytosis and melanoma.

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Section: Intr Acellul Ar Reg Ul Ation Of K Itlgmentioning

confidence: 99%

Section: Intracellular Regulation Of Kitlgmentioning

confidence: 99%

Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases

Sevilla,

Grichnik

2024

Experimental Dermatology

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“…c-KIT Ligand (KITLG), commonly known as Stem Cell Factor (SCF), is a potent cell growth regulator. Acting primarily as a ligand by binding to c-KIT, it presents significant biological activities on an array of tissue cells [4][5][6], including hematopoietic stem cells, pigment cells, germ cells, and tumor cells. Evidence suggests that KITLG performs an essential role in numerous cancers.…”

Section: Introductionmentioning

confidence: 99%

Exploring the biological behavior and underlying mechanism of KITLG in triple-negative breast cancer

Qin,

Li,

Huang

et al. 2024

J. Cancer

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The tyrosine-kinase receptor that is specified by the KIT locus is demarcated by KITLG. This multifaceted factor is instrumental during in-utero germ and neural cell maturation and hematopoiesis, ostensibly reflecting its role in facilitating cell migration. Concurrently, KITLG is prone to a mutation in germ cell tumors, entailing a presumed connection to tumorigenesis. Despite this, the intricacies of its function in breast cancer and the relevant mechanisms remain elusive. Multiple independent databases depict a consistently low expression of KITLG within tissues affected by triple-negative breast cancers (TNBC), a trend strongly coupled with reduced survival rates. Interestingly, non-triple-negative breast cancers exhibit a markedly high expression of KITLG compared to the norm. An initial analysis of the GEO database speculates that KITLG may serve as an oncogene suppressor in TNBC, hinting at varied roles for KITLG isoforms within this disease context. In conclusion, our preliminary analysis offers valuable insights into the role and expression pattern of KITLG in TNBC. We provide evidence supporting its consideration as a promising new prognostic marker, thereby potentially enriching therapeutic strategies for TNBC. Indeed, given the limited advances in molecularly targeted therapy for TNBC, a significant need exists for a more precise therapeutic approach and a comprehensive understanding of its inherent mechanisms of action.

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DAZAP1 Phase Separation Regulates Mitochondrial Metabolism to Facilitate Invasion and Metastasis of Oral Squamous Cell Carcinoma

Zhang,

Ni,

Zhang

et al. 2024

Cancer Research

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Tumor invasion and metastasis are the underlying causes of the high mortality rate of oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ associated protein 1 (DAZAP1), as a tumor-promoting factor with an important role in OSCC progression. DAZAP1 was significantly upregulated in OSCC, which enhanced the migration and invasion of OSCC cells and induced the epithelial-mesenchymal transition (EMT). RNA-seq analysis and experimental validation demonstrated that DAZAP1 regulates mitochondrial energy metabolism in OSCC. Mechanistically, DAZAP1 underwent liquid-liquid phase separation (LLPS) to accumulate in the nucleus where it enhanced cytochrome-c oxidase 16 (COX16) expression by regulating pre-mRNA alternative splicing, thereby promoting OSCC invasion and mitochondrial respiration. In mouse OSCC models, loss of DAZAP1 suppressed EMT, downregulated COX16, and reduced tumor growth and metastasis. In OSCC patient samples, expression of DAZAP1 positively correlated with COX16, and high expression of both proteins was associated with poor patient prognosis. Together, these findings revealed a mechanism by which DAZAP1 supports mitochondrial metabolism and tumor development of OSCC, suggesting the potential of therapeutic strategies targeting DAZAP1 to block OSCC invasion and metastasis.

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DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway

Cited by 4 publications

References 33 publications

Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases

Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases

Exploring the biological behavior and underlying mechanism of KITLG in triple-negative breast cancer

DAZAP1 Phase Separation Regulates Mitochondrial Metabolism to Facilitate Invasion and Metastasis of Oral Squamous Cell Carcinoma

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