PHLDA3

Last update 08 May 2025

Basic Info

Synonyms

PHLDA3, pleckstrin homology like domain family A member 3, Pleckstrin homology-like domain family A member 3

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Introduction

p53/TP53-regulated repressor of Akt/AKT1 signaling. Represses AKT1 by preventing AKT1-binding to membrane lipids, thereby inhibiting AKT1 translocation to the cellular membrane and activation. Contributes to p53/TP53-dependent apoptosis by repressing AKT1 activity. Its direct transcription regulation by p53/TP53 may explain how p53/TP53 can negatively regulate AKT1. May act as a tumor suppressor.

100 Clinical Results associated with PHLDA3

100 Translational Medicine associated with PHLDA3

0 Patents (Medical) associated with PHLDA3

Literatures (Medical) associated with PHLDA3

01 May 2025·Free Radical Biology and Medicine

Estrogen mitigates ischemia-reperfusion injury by inhibiting cardiomyocyte ferroptosis through the downregulation of PHLDA3 expression

Article

Author: Lin, Yutong ; Gao, Chuanyu ; Hu, Jiayi ; Tao, Yecheng ; Yang, Honghui ; Zhu, Lijie ; Zhu, Qiongjun ; Zhang, Wenbin ; Chen, Zhezhe ; Wang, Dan'an

Ferroptosis represents a significant target for mitigating myocardial ischemia-reperfusion (I/R) injury. Existing literature indicates that estrogen (17β-estradiol, E2) can alleviate such injuries through various pathways. However, the specific mechanisms by which E2 may confer protection against myocardial I/R injury through the inhibition of ferroptosis remain to be fully elucidated. This study employed a mouse model of left anterior descending coronary artery ligation to investigate the protective effects of E2 on myocardial I/R injury, with a particular focus on its inhibitory effects on ferroptosis and PHLDA3 in both hypoxia-reoxygenation (H/R) and I/R models. A bioinformatics analysis was conducted to evaluate the impact of estrogen receptor GPER knockout on PHLDA3 expression and ferroptosis. Loss-of-function approaches were employed to elucidate the role of PHLDA3 in ferroptosis during myocardial I/R injury. Our findings demonstrate that E2 can ameliorate myocardial I/R injury, primarily by inhibiting ferroptosis. Notably, PHLDA3 expression levels were significantly elevated during ischemia-reperfusion events; however, E2 was observed to suppress this expression. Bioinformatics analysis indicated that PHLDA3 levels increased following GPER knockdown, and the inhibitory effect of E2 on PHLDA3 expression could be partially reversed by GPER inhibitors (G15) in animal models. Furthermore, the suppression of PHLDA3 reduced ferroptosis and mitigated the severity of myocardial I/R injury. Utilizing mass spectrometry and co-immunoprecipitation methodologies, we have elucidated a potential mechanism in which PHLDA3 directly binds to and interacts with proteins involved in the process of ferroptosis. Our findings demonstrate that E2 effectively suppresses ferroptosis and mitigates myocardial I/R injury by downregulating PHLDA3 expression through the activation of the GPER receptor.

01 Jan 2025·Indian Journal of Otolaryngology and Head & Neck Surgery

Evaluation of Methylation and Changes in the Transcriptomics and Proteomics of the GRHL3, PHLDA3, and in Patients with Head and Neck Squamous Cell Carcinoma

Article

Author: Idani, Asra ; Mokhtari, Zahra ; Derakhshan, Alireza ; Tabari, Azin ; Saffarzadeh, Negin ; Siahbani, Sarah ; Hosseinpour Aghaei, Mahdi ; Zohourian Shahzadi, Shahriar ; Aghazadeh, Keyvan ; Azarian, Maryam ; Lotfi, Maryam ; Moghadam Fard, Atousa ; Motamedi, Salar ; Farmani, Shiva ; Maddahi, Moein ; Shakoori, Abbas ; Azani, Alireza

IntroductionHead and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common malignancy in the world. High mortality and severe complications are critical features of head and neck cancer. Changes in intracellular signaling pathways are a general tumor formation and progression mechanism. Due to the objectivity that the PI3K pathway plays a critical role in HNSCC. the negative regulators involved in this pathway such as GRHL3, PHLDA3, which have been reported to reduce their expression in malignancies, can achieve significant results in the detection, prognosis, and targeted treatment of HNSCC if changes in transcriptome, proteome, and methylation levels of these genes are observed.Method45 fresh head and neck cancer cells and 45 control samples were collected. Protein expression was also studied using Western blot. Additionally, promoter methylation was investigated using the qMSP method to observe changes in the regulatory regions.ResultsThe results indicate a significant decrease in GRHL3 expression and a significant increase in PHLDA3 expression. Notably, these expression changes were not confirmed at the protein level. Additionally, methylation analysis revealed hypermethylation of the promoter region in GRHL3 and hypomethylation in PHLDA3.ConclusionThis study is the first to examine the genes GRHL3 and PHLDA3 at the transcriptome, proteome, and promoter methylation levels. Based on the results, we hope that further studies will confirm the potential of GRHL3 and PHLDA3 as prognostic biomarkers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12070-024-05057-0.

02 Jul 2024·Brain Communications

Inhibition of PHLDA3 expression in human superoxide dismutase 1-mutant amyotrophic lateral sclerosis astrocytes protects against neurotoxicity

Article

Author: Řehořová, Monika ; Abdelgawad, Mai ; Szebényi, Kornélia ; Petrova, Veselina ; Vargová, Ingrid ; Jendelová, Pavla ; Kwok, Jessica C F ; Fawcett, James W ; Sándor, Alexandra ; Lakatos, András ; Marekova, Dana ; Turečková, Jana ; Gibbons, George M

AbstractPleckstrin homology-like domain family A—member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin homology-like domain family A—member 3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of pleckstrin homology-like domain family A—member 3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that pleckstrin homology-like domain family A—member 3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced ALS and even control spinal astrocytes with a lower pleckstrin homology-like domain family A—member 3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing pleckstrin homology-like domain family A—member 3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.

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PHLDA3

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