FHL2 interacts with iASPP and impacts the biological functions of leukemia cells

Lu, Weiyue; Yu, Tengteng; Liu, Shuang; Li, Saisai; Li, Shouyun; Liu, Jia; Xu, Yingxi; Xing, Haiyan; Tian, Zheng; Tang, Kejing; Rao, Qing; Wang, Jianxiang; Wang, Min

doi:10.18632/oncotarget.16617

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…Indeed, there is growing evidence that overexpression, rather than mutation, of iASPP conveys its oncogenic properties. In addition to our previous characterization in p53 wild-type breast cancer (32), elevated iASPP levels have recently been reported in multiple human cancers, including bladder cancer (63), non-small-cell lung cancer (64), ovarian clear cell carcinoma (65), colorectal cancer (66), and particularly in acute leukemia where p53 mutations are relatively rare (67, 68).…”

Section: Discussionmentioning

confidence: 69%

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Chen

Zhong

et al. 2019

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

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The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53–iASPP crystal structure reveals that iASPP displaces the p53 L1 loop—which mediates sequence-specific interactions with the signature-corresponding base—without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF–DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain—except the oncogenic E6 from human papillomaviruses (HPVs)—structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.

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Section: Discussionmentioning

confidence: 69%

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Chen

Zhong

et al. 2019

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

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“…Based on the functional diversity of LIM structural domains, FHL2 can interact with various proteins and thus play an important role in cell proliferation, differentiation, and signaling [ 74 , 75 ]. Findings suggest that the interaction of FHL2 and iASPP inhibits apoptosis and promotes cell proliferation [ 76 ]. If FHL2 is knocked out, then it causes the cell cycle to stay in the G0/G1 phase, thereby inhibiting cell proliferation [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Human Cell Cycle Phase Markers Based on Single-Cell RNA-Seq Data by Using Machine Learning Methods

Huang

Lei

Guo

et al. 2022

BioMed Research International

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The cell cycle is composed of a series of ordered, highly regulated processes through which a cell grows and duplicates its genome and eventually divides into two daughter cells. According to the complex changes in cell structure and biosynthesis, the cell cycle is divided into four phases: gap 1 (G1), DNA synthesis (S), gap 2 (G2), and mitosis (M). Determining which cell cycle phases a cell is in is critical to the research of cancer development and pharmacy for targeting cell cycle. However, current detection methods have the following problems: (1) they are complicated and time consuming to perform, and (2) they cannot detect the cell cycle on a large scale. Rapid developments in single-cell technology have made dissecting cells on a large scale possible with unprecedented resolution. In the present research, we construct efficient classifiers and identify essential gene biomarkers based on single-cell RNA sequencing data through Boruta and three feature ranking algorithms (e.g., mRMR, MCFS, and SHAP by LightGBM) by utilizing four advanced classification algorithms. Meanwhile, we mine a series of classification rules that can distinguish different cell cycle phases. Collectively, we have provided a novel method for determining the cell cycle and identified new potential cell cycle-related genes, thereby contributing to the understanding of the processes that regulate the cell cycle.

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“…These same variants are in LD and have additionally been associated with myelopoiesis and hematopoiesis [69]. As indicated above, FHL2 is often encountered in the context of oncology, and a large body of research implicates FHL2 in the development of leukemia [69][70][71][72][73]. Several of these studies showed that increased FHL2 expression correlates with poor prognosis of leukemia [69,70].…”

Section: Fhl2 Snps In Coagulation and Cancermentioning

confidence: 95%

How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

Habibe

Clemente-Olivo

Vries

2021

Cells

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Susceptibility to complex pathological conditions such as obesity, type 2 diabetes and cardiovascular disease is highly variable among individuals and arises from specific changes in gene expression in combination with external factors. The regulation of gene expression is determined by genetic variation (SNPs) and epigenetic marks that are influenced by environmental factors. Aging is a major risk factor for many multifactorial diseases and is increasingly associated with changes in DNA methylation, leading to differences in gene expression. Four and a half LIM domains 2 (FHL2) is a key regulator of intracellular signal transduction pathways and the FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging. Remarkably, FHL2 expression increases with methylation. This was demonstrated in relevant metabolic tissues: white adipose tissue, pancreatic β-cells, and skeletal muscle. In this review, we provide an overview of the current knowledge on regulation of FHL2 by genetic variation and epigenetic DNA modification, and the potential consequences for age-related complex multifactorial diseases.

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FHL2 interacts with iASPP and impacts the biological functions of leukemia cells

Cited by 8 publications

References 32 publications

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Identification of Human Cell Cycle Phase Markers Based on Single-Cell RNA-Seq Data by Using Machine Learning Methods

How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

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