#tetramers

[whats-in-a-sentence]

The MADS box genes share a characteristic, conserved nucleotide sequence known as a MADS box, which encodes a protein structure known as the MADS domain (Figure 20.28A). (...) When the tetramers bind two different CArG-boxes on the same target gene, the boxes are brought into close proximity, causing DNA bending (Figure 20.28B). (...) These tetramers are hypothesized to bind CArG-boxes on target genes and modify their expression (see Figure 20.28 B).

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[tenth-sentence]

According to the model, tetramers composed of different homodimers and heterodimers of MADS domain proteins can exert combinatorial control over floral organ identity.

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[i-am-q]

Those that were allowed to use the ATP battery in my brain for their “double blind” study up until Jan. 2024, I respect you but respectfully ask for full control of my body again—whatever that means.

Those with access to the slave cameras through the company, keep it up (A plus as they say). The world is behind you.

[covid-safer-hotties]

SARS-CoV-2-specific CD8+ T cells from people with long COVID establish and maintain effector phenotype and key TCR signatures over 2 years - Published Sept 16, 2024

Significance Long COVID occurs in small but important minority of patients following COVID-19, reducing quality of life and contributing to healthcare burden. Although research into underlying mechanisms is evolving, immunity is understudied. As the recall of T cell memory promotes more rapid recovery and ameliorates disease outcomes, establishment of robust memory T cells is important for protection against subsequent infections, even when the virus mutates. We defined how SARS-CoV-2-specific T cell and B cell responses are established and maintained following infection and vaccination for 2 y in people with long COVID. We found robust and prototypical SARS-CoV-2-specific T cells with effector phenotype and key T cell receptor signatures in people with long COVID following SARS-CoV-2 infection and subsequent COVID-19 vaccination.

Abstract Long COVID occurs in a small but important minority of patients following COVID-19, reducing quality of life and contributing to healthcare burden. Although research into underlying mechanisms is evolving, immunity is understudied. SARS-CoV-2-specific T cell responses are of key importance for viral clearance and COVID-19 recovery. However, in long COVID, the establishment and persistence of SARS-CoV-2-specific T cells are far from clear, especially beyond 12 mo postinfection and postvaccination. We defined ex vivo antigen-specific B cell and T cell responses and their T cell receptors (TCR) repertoires across 2 y postinfection in people with long COVID. Using 13 SARS-CoV-2 peptide–HLA tetramers, spanning 11 HLA allotypes, as well as spike and nucleocapsid probes, we tracked SARS-CoV-2-specific CD8+ and CD4+ T cells and B-cells in individuals from their first SARS-CoV-2 infection through primary vaccination over 24 mo. The frequencies of ORF1a- and nucleocapsid-specific T cells and B cells remained stable over 24 mo. Spike-specific CD8+ and CD4+ T cells and B cells were boosted by SARS-CoV-2 vaccination, indicating immunization, in fully recovered and people with long COVID, altered the immunodominance hierarchy of SARS-CoV-2 T cell epitopes. Meanwhile, influenza-specific CD8+ T cells were stable across 24 mo, suggesting no bystander-activation. Compared to total T cell populations, SARS-CoV-2-specific T cells were enriched for central memory phenotype, although the proportion of central memory T cells decreased following acute illness. Importantly, TCR repertoire composition was maintained throughout long COVID, including postvaccination, to 2 y postinfection. Overall, we defined ex vivo SARS-CoV-2-specific B cells and T cells to understand primary and recall responses, providing key insights into antigen-specific responses in people with long COVID.

[sci-memes-yura15cbx]

Оригинальный анекдот:

Точечная мутация в 6 кодоне гена β-цепи глобина приводит к замещению глютаминовой кислоты на валин. Включение βs-цепи в тетрамер приводит к образованию Hbs. Нерастворимость деоксигенированного Hbs приводит к его полимеризации и, как следствие, к снижению деформабельности и образованию серповидных эритроцитов - Серповидноклеточной анемии.

Алё, это Генадий Петрович?

Нет, это Мухрат Ибрагимович

А это номер 25-36-77 ?

Нет, 25-36-78.

Надо же, ошибка 6-м знаке и такой эффект!

***

Original joke:

A point mutation in codon 6 of the globin β-chain gene results in the substitution of glutamic acid for valine. The incorporation of the βs chain into the tetramer leads to the formation of Hbs. The insolubility of deoxygenated Hbs leads to its polymerization and, consequently, to a decrease in deformability and the formation of sickle-shaped erythrocytes - sickle cell anemia.

Hello, is this Moishe?

No, this is Muhammad.

Is this number 25-36-77?

No, 25-36-78.

Wow, an error on the 6th sign and such an effect!

***

chiste original:

Una mutación puntual en el codón 6 del gen de la cadena β de la globina da como resultado la sustitución del ácido glutámico por valina. La incorporación de la cadena βs en el tetrámero conduce a la formación de Hbs. La insolubilidad de la Hbs desoxigenada conduce a su polimerización y, en consecuencia, a una disminución de la deformabilidad y la formación de eritrocitos en forma de hoz: anemia de células falciformes.

Hola, ¿es Moishe?

No, este es Mahoma.

¿Este es el número 25-36-77?

No, 25-36-78.

¡Vaya, un error en el sexto signo y tal efecto!

Ошибка 6-м знаке и такой эффект!

Error 6th sign and such an effect!

¡Error en el sexto signo

Мои мемы my memes

[moleculardepot]

Native Rabbit Pyruvate Kinase

Native Rabbit Pyruvate Kinase Catalog number: B2017310 Lot number: Batch Dependent Expiration Date: Batch dependent Amount: 25 kU Molecular Weight or Concentration: 237 kDa, tetramer of four identical subunits 57 kDa Supplied as: Powder Applications: a molecular tool for various biochemical applications Storage: −20°C Keywords: Pyruvate kinase PKM, Pyruvate kinase muscle isozyme, ATP: Pyruvate…

[mblinternationalcorporation]

Non-Classical MHC Tetramers in Health and Disease: Emerging Trends

Major Histocompatibility Complex (MHC) molecules are essential components of the immune system, playing a crucial role in antigen presentation and immune response. Traditionally, research has focused on classical MHC molecules (MHC class I and II). However, recent advances have highlighted the significance of non-classical MHC molecules, specifically non-classical MHC tetramers, in health and disease. These molecules have distinct structural and functional properties that differentiate them from their classical counterparts, offering new insights and therapeutic possibilities in immunology.

Understanding Non-Classical MHC Molecules

Non-classical MHC molecules, including HLA-E, HLA-F, HLA-G in humans, and their murine equivalents (Qa-1, Qa-2, and others), exhibit limited polymorphism compared to classical MHC molecules. They are expressed in specific tissues and have unique roles in immune regulation, such as tolerance induction and modulation of immune responses. Non-classical MHC molecules present a broader range of antigens, including non-peptidic antigens, lipids, and small molecules, to specialized subsets of T cells and natural killer (NK) cells.

Structure and Function of Non-Classical MHC Tetramers

Non-classical MHC tetramers are complexed structures composed of four MHC molecules bound to specific antigens, forming a tetramer that can be used to stain antigen-specific T cells. These tetramers are valuable tools for studying the immune response, allowing researchers to track and characterize antigen-specific T cells with high precision. Unlike classical MHC tetramers, non-classical MHC tetramers often interact with non-peptidic antigens and can engage with both T cell receptors (TCRs) and NK cell receptors, broadening their functional scope.

Antigen Presentation

One of the primary functions of non-classical MHC tetramers is to present antigens to T cells and NK cells. For instance, HLA-E tetramers present peptides derived from the leader sequences of other MHC class I molecules, interacting with the CD94/NKG2 receptor on NK cells and some T cells. This interaction plays a crucial role in immune surveillance and the regulation of NK cell activity, contributing to the recognition of infected or transformed cells.

Immune Regulation

Non-classical MHC tetramers also contribute to immune regulation. HLA-G tetramers, for example, are involved in immune tolerance, particularly during pregnancy. HLA-G expression on trophoblasts helps to protect the fetus from maternal immune attack by interacting with inhibitory receptors on NK cells and T cells. This immune modulatory function is critical for maintaining a healthy pregnancy and preventing autoimmune responses.

Non-Classical MHC Tetramers in Health

Infection

Non-classical MHC tetramers play vital roles in the immune response to infections. For instance, HLA-E tetramers can present viral peptides to NK cells, enhancing their ability to recognize and eliminate infected cells. This mechanism is particularly important in viral infections where pathogens downregulate classical MHC molecules to evade immune detection. By presenting conserved viral peptides, non-classical MHC molecules ensure the immune system can still identify and respond to infected cells.

Cancer

In the context of cancer, non-classical MHC tetramers offer promising therapeutic avenues. Tumors often exploit immune checkpoints and inhibitory pathways to evade immune surveillance. HLA-G tetramers, which interact with inhibitory receptors on immune cells, are frequently upregulated in various cancers. Understanding this interaction has led to the development of strategies to block HLA-G mediated immune suppression, enhancing the anti-tumor immune response. Additionally, non-classical MHC tetramers can be used to identify tumor-specific T cells, facilitating the development of targeted immunotherapies.

Autoimmunity and Tolerance

Non-classical MHC tetramers are also implicated in autoimmune diseases and immune tolerance. For example, the expression of HLA-G and its interaction with immune inhibitory receptors is associated with the regulation of autoimmune responses. By promoting tolerance, non-classical MHC molecules help to prevent excessive immune activation that can lead to tissue damage in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Non-Classical MHC Tetramers in Disease

Viral Infections

In viral infections, pathogens often evolve mechanisms to evade classical MHC-mediated immune responses. Non-classical MHC molecules provide an alternative pathway for immune recognition. For instance, HCMV (human cytomegalovirus) downregulates classical MHC class I molecules to avoid detection by cytotoxic T lymphocytes (CTLs). However, HLA-E tetramers can present viral peptides to NK cells, compensating for the loss of classical MHC presentation and maintaining immune pressure on the virus.

Cancer Immune Evasion

Cancer cells frequently upregulate non-classical MHC molecules to escape immune detection. HLA-G expression, for example, is associated with poor prognosis in various cancers, including ovarian, breast, and colorectal cancers. By interacting with inhibitory receptors on immune cells, HLA-G tetramers suppress anti-tumor immune responses, facilitating tumor growth and metastasis. Understanding these interactions has prompted the development of therapeutic strategies aimed at blocking HLA-G and restoring effective immune surveillance.

Autoimmune Diseases

Autoimmune diseases result from an imbalance in immune regulation, where the immune system mistakenly targets self-tissues. Non-classical MHC molecules like HLA-G play a protective role by promoting immune tolerance. In diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, altered expression of HLA-G has been observed. Therapeutic modulation of HLA-G expression and function holds potential for restoring immune balance and mitigating autoimmune pathology.

Emerging Trends and Future Directions

Novel Tetramer Technologies

Recent advancements in tetramer technology have expanded the capabilities of non-classical MHC tetramers. Innovations include the development of multi-antigen tetramers, which can present multiple antigens simultaneously, enhancing the detection of diverse T cell populations. Additionally, improvements in tetramer stability and affinity have increased their utility in clinical and research settings.

Immunotherapy Applications

The unique properties of non-classical MHC tetramers make them attractive candidates for immunotherapy. By targeting specific immune pathways and cell populations, non-classical MHC tetramers can be used to design personalized immunotherapies for cancer and autoimmune diseases. For example, blocking HLA-G interactions or enhancing HLA-E-mediated immune responses are promising strategies for boosting anti-tumor immunity and regulating autoimmune reactions.

Biomarker Discovery

Non-classical MHC tetramers hold potential as biomarkers for disease diagnosis and prognosis. Elevated levels of HLA-G, for instance, are associated with poor outcomes in cancer patients. Monitoring non-classical MHC tetramer expression and function can provide valuable insights into disease progression and treatment efficacy. As research advances, the identification of novel biomarkers will enhance our ability to diagnose and treat various immune-related conditions.

Conclusion

Non-classical MHC tetramers represent a fascinating and rapidly evolving field in immunology. Their unique structural and functional characteristics distinguish them from classical MHC molecules, offering new insights into immune regulation and disease mechanisms. From infection and cancer to autoimmunity and tolerance, non-classical MHC tetramers play pivotal roles in health and disease. Emerging trends in tetramer technology, immunotherapy, and biomarker discovery promise to unlock new therapeutic possibilities and improve our understanding of the immune system. As research continues to unfold, non-classical MHC tetramers will undoubtedly remain at the forefront of immunological innovation.

[12nb34]

📆 Jan 2023 📰 Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion 🗞 Frontiers

Determining which antigens are targeted in SARS-CoV-2 ESNs provides insight into mechanisms of response. T-cells targeting the replication-transcription complex (RTC) of SARS-CoV-2 were described by Swadling et al. (2022) in ESNs (7). The RTC is comprised of the RNA polymerase NSP12, a co-factor NSP7, and the helicase NSP13 (37). Its expression early in the SARS-CoV-2 replication cycle makes the RTC a target for rapidly-induced T-cell responses (7). The authors identified fivefold-higher RTC-specific T-cell responses in ESNs compared to unexposed controls. Furthermore, cellular immunity in ESNs preferentially targeted the RTC over structural proteins compared to seropositive individuals. However, the authors did not assay cellular responses to other NSPs.

In a study of six ESN sexual partners of HSV-2-infected individuals by Posavad et al. (2010), T cell responses in ESNs were skewed towards peptides expressed early in the virus replication cycle, whereas HSV-2 seropositive individuals more frequently generated responses to structural proteins present in virions. The authors speculated that this skew in ESNs reflected early T-cell engagement with infected cells before the production of infectious virions. Together, these data support a model whereby rapid T-cell responses targeting early translated NSPs may prevent infection from gaining a foothold.

To prevent infection before seroconversion, a rapid cellular response appears critical. Chandran et al. (2021) assayed weekly nasopharyngeal swabs and blood samples from HCWs, and demonstrated that SARS-CoV-2 specific T-cell proliferation can occur before PCR positivity (42). These rapid responses may originate from pre-existing, cross-reactive T-cells specific for human coronaviruses (HCoVs). Cross-recognition of SARS-CoV-2 by HCoV-specific T-cells has been widely described (43–50), and T-cells from COVID-19 convalescents preferentially target conserved epitopes over SARS-CoV-2-specific epitopes (49). HCWs display higher levels of HCoV-specific T-cells than community controls (28), which may contribute to the abundance of ESNs amongst HCWs. The activation of cross-reactive T-cells by related viruses has been termed ‘heterologous immunity’ (51). This is distinct from autologous viral infection in that neutralising antibody responses to the heterologous virus may be suboptimal, allowing cellular memory to dominate.

The RTC is highly conserved between SARS-CoV-2 and HCoVs (7). Tetramer staining of T-cells with an HCoV-HKU1 homologue of the RTC component NSP7 showed strong responses in SARS-CoV-2 ESNs. Swadling et al. (2022) suggested that prior exposure to HCoV-HKU1 generates cross-reactive T-cells specific for NSP7, enabling rapid abortion of SARS-CoV-2 infection (7). A study of camel workers in Saudi Arabia identified both CD4+ and CD8+ responses to Middle-East Respiratory Syndrome coronavirus in four highly-exposed seronegative individuals, suggesting that the ESN phenomenon may be common to other human-infective coronaviruses.

Cellular immunity is able to clear SARS-CoV-2 infection in isolation; patients with X-linked agammaglobulinemia who cannot produce antibodies eventually clear SARS-CoV-2 infection, and mount higher magnitude CD8+ T-cell responses to SARS-CoV-2 compared to immunocompetent individuals (54). However, in Wang et al. (2021) the magnitude of the SARS-CoV-2-specific CD4+ T-cell response was twice as high in infected individuals compared to ESNs. This casts doubt on their role in protection against infection.

[selkypostergirl]

I promise it looks like hexavalent carbon on first blush but it really isn’t! It’s a weird tetramer with a delocalized electron system

Check out the 3D model, it’s a really good way to see the weird way the bonding works

Organometallic chemistry is a beautiful lawless land

Fundamentally there’s 2 kinds of scary chemistry:

The kind that scares laypeople

And the kind that scares chemists

[mblinternationalcorporation]

Non-Classical MHC Tetramers: Expanding Insights into Immune Recognition

Major histocompatibility complex (MHC) molecules play a pivotal role in the immune system by presenting antigenic peptides to T cells, thereby initiating immune responses against pathogens and abnormal cells. While classical MHC molecules (e.g., MHC class I and class II) are well-studied for their roles in antigen presentation, non-classical MHC molecules have gained increasing attention for their diverse functions in immune recognition. Non-classical MHC tetramers represent a sophisticated tool that has significantly contributed to our understanding of these molecules, offering insights into their roles in both innate and adaptive immunity. This article explores the significance, applications, and recent advancements in non-classical MHC tetramers, emphasizing their expanding role in immune recognition.

The Role of MHC Molecules in Immune Recognition

MHC molecules are glycoproteins expressed on the surface of cells, where they present peptide antigens to T cells. This process is crucial for T cell receptor (TCR) recognition and subsequent activation of adaptive immune responses. Classical MHC class I molecules present peptides derived from intracellular pathogens to CD8+ cytotoxic T cells, while MHC class II molecules present peptides from extracellular pathogens to CD4+ helper T cells. Beyond these classical functions, non-classical MHC molecules exhibit unique characteristics that broaden their roles in immune surveillance and regulation.

Non-Classical MHC Molecules: Diversity and Functions

Non-classical MHC molecules are structurally distinct from classical MHC molecules and often exhibit specialized functions that extend beyond conventional antigen presentation. Some notable examples include:

MHC class Ib molecules: Such as HLA-E, HLA-G, and CD1 molecules, which present non-peptide antigens or unconventional peptides to T cells and other immune cells.

MR1 molecules: Presenting microbial vitamin B metabolites to mucosal-associated invariant T (MAIT) cells, linking innate and adaptive immune responses.

H2-M3 molecules: Presenting glycolipid antigens to natural killer T (NKT) cells, regulating immune responses in infections and cancer.

These molecules play critical roles in immune tolerance, response to stress signals, and modulation of immune cell activity, highlighting their importance in both health and disease contexts.

Advancements in Non-Classical MHC Tetramers

Non-classical MHC tetramers are synthetic multimeric complexes that incorporate non-classical MHC molecules and specific peptide antigens. They have become indispensable tools for studying and manipulating immune responses in various experimental settings. Key advancements include:

Specificity and Sensitivity: Non-classical MHC tetramers allow for the precise detection and characterization of antigen-specific T cells with high sensitivity, facilitating the identification of rare T cell populations involved in immune responses.

Customization: Researchers can customize non-classical MHC tetramers by selecting specific peptide antigens or non-peptide ligands, enabling the study of diverse T cell subsets and their roles in different immunological contexts.

Multiplexing: Advances in flow cytometry and imaging techniques have enabled the simultaneous detection of multiple non-classical MHC tetramers labeled with distinct fluorophores, expanding the scope of immune profiling and analysis.

Functional Studies: Beyond T cell identification, non-classical MHC tetramers allow functional studies, such as assessing cytokine production, cytotoxicity, and activation states of antigen-specific T cells, providing deeper insights into immune responses.

Applications of Non-Classical MHC Tetramers

Non-classical MHC tetramers have diverse applications across immunology and beyond:

Infectious Diseases: Studying antigen-specific T cell responses against viral, bacterial, and parasitic infections, including chronic infections where unconventional T cell subsets may play critical roles.

Cancer Immunotherapy: Identifying tumor-specific T cells and assessing their functional properties for developing personalized immunotherapies.

Autoimmune Diseases: Characterizing self-reactive T cells and understanding their contributions to autoimmune pathogenesis and tolerance mechanisms.

Transplantation: Evaluating alloreactive T cell responses and monitoring graft rejection or tolerance in transplant recipients.

Challenges and Future Directions

Despite their utility, challenges remain in the development and application of non-classical MHC tetramers:

Complexity of Ligand Binding: Non-classical MHC molecules often bind diverse ligands with varying affinities, requiring careful selection and characterization of peptide antigens or non-peptide ligands for tetramer design.

Technological Advancements: Continued advancements in tetramer technology, such as enhancing tetramer stability, improving detection sensitivity, and expanding multiplexing capabilities, will further enhance their utility in immune profiling and therapeutic development.

Clinical Translation: Bridging the gap between basic research and clinical applications by validating the relevance of non-classical MHC tetramer findings in human diseases and translating them into diagnostic and therapeutic strategies.

Conclusion

Non-classical MHC tetramers have emerged as invaluable tools for dissecting the complex landscape of immune recognition mediated by non-classical MHC molecules. From fundamental studies of immune cell biology to applied research in immunotherapy and infectious diseases, these tetramers continue to expand our understanding of immune responses and hold promise for future clinical applications. As technology advances and our knowledge deepens, non-classical MHC tetramers will undoubtedly play a pivotal role in advancing immunology and improving human health.

[medchemexpressinhibitor-blog]

Deciphering the mechanism of p53-mediated ferroptosis

Background of p53

It is well known that p53 is a tumor suppressor gene and essential for regulating DNA repair and cell division. Since its discovery in 1979, p53 gene has been a hot topic in molecular biology and oncology. According to Dolgin, E. et al.’s literature published in Nature, TP53 becomes the most popular human genome in the list of most studied genes in PubMed database[1]. The TP53 gene provides instructions for making a p53 protein.

According to integrated cancer genomic and epidemiological data analyses, TP53 is the most commonly mutated gene (35%) among mutated driver genes in human cancers[2](Figure 1), it is also the most studied gene in the human genome based on PubMed database. TP53 is located on the short arm of human chromosome 17 and encodes the p53 tumor suppressor protein.

The p53 protein is often referred to as the “Guardian of the Genome”. The main biological function of the p53 protein is the protection of the DNA integrity of the cell.

Figure 1: Left, List of most studied genes in the PubMed database as of 2017

[3]

Right, Proportion of epidemiologically weighted gene mutations in important genomes in the cancer patient population

[2]

In response to intrinsic and extrinsic stress signals, the p53 protein is activated by a variety of post-translational modifications including phosphorylation, acetylation, methylation, ubiquitination, or SUMOylating, etc. These modifications at key sites allow p53 protein to become stabilized, oligomerize as a tetramer, interact with cofactors, bind to the p53RE, execute the transcription of the target genes in a tightly controlled and context dependent manner [Figure 2]. In recent years it was found that p53 plays roles in the regulation of ferroptosis. In this article, the connection between p53 and ferroptosis will be explored.

Figure 2. Central role of p53 protein as a tumor suppressor

[4]

Ferroptosis is a novel form of regulated cell death. The morphological features of ferroptosis include shrunk mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and rupture of outer mitochondrial membrane. The p53 (especially acetylation-defective mutant p53, p533KR) positively regulates ferroptosis by inhibiting expression of SLC7A11 (a specific light-chain subunit of the cysteine/glutamate antiporter).

SLC7A11 is a subunit of System Xc-, which is responsible for maintaining redox homeostasis by importing cystine. After transported into cells, cystine is quickly reduced to cysteine, a critical precursor for glutathione and subsequent reduced glutathione (GSH). GSH biosynthesis is critical to functional activity of membrane lipid repair enzyme GPX4. Inhibiting System Xc- activity by inhibition of SLC7A11 expression leads to decreased uptake of cystine, eventually resulting in impaired antioxidant capability of cells and initiation of ferroptosis [Figure 3]. “Ferroptosis as a p53-mediated activity during tumor suppression”, Jiang et al. reported that p53 inhibits expression of SLC7A11, reduces cystine uptake and induces ferroptosis of cancer cells.

Figure 3: The mechanism of p53 mediated ferroptosis

[6]

.The SLC7A11 gene is a target of p53-mediated transcriptional repression

Jiang, L et al. has demonstrated in the "Ferroptosis as a p53-mediated Activity during Tumour Suppression" published in Nature in 2015 demonstrates that p53 supposes SLC7A11 (a key component of the cystine/glutamate antitransporter) to inhibit cystine uptake and sensitize cells to ferroptosis[7].

By microarray analysis of Tetracycline -controlled (tet-on) p53 induced and non-induced cells, SLC7A11 was identified as a novel p53 target gene. Western blot showed that p53 activation significantly reduced SLC7A11 protein levels [Figure 4a]. While in U2OS cells under p53-knockdown conditions treated Nutlin-3 (a p53-MDM2 inhibitor), downregulation of SLC7A11 was abrogated. These data suggest that SLC7A11 gene is a target of p53-mediated transcriptional repression.

The acetylation defective mutant p533KR cells that fails to induce cell cycle arrest, senescence and apoptosis maintain the ability to regulate SLC7A11 expression and induce ferroptosis. Tet-on p533KR inducible H1299 cells were resistant to erastin-mediated ferroptosis in the absence of p533KR induction, while significant cell death was observed upon p533KR induction together with Erastin treatment. But SLC7A11overexpression abrogated p533KR induced ferroptosis [Figure 4c]. In xenograft tumor models implanted with p53-null H1299 cells, tumor size is markedly reduced upon p533KR expression induced by tetracycline, while this tumor suppression effects of p533KR were abrogated by SLC7A11 overexpression[7] [Figure 4d-e].

Figure 4. SLC7A11 regulates p53-mediated ferroptosis

[7]

a: Western blot of Doxycycline-treated tet-on p53 stable line cells; b: Western blot analysis of Nutlin-treated p53-knockdown U2OS cells; c-d: Ferroptosis in Tet-on p53

3KR

cells transfected with a control or SLC7A11-overexpressing plasmid and xenograft tumor weight of cells.

In addition, it was found that high levels of reactive oxygen species (ROS) can trigger p53-mediated ferroptosis. As shown in Figure 5a, no significant cell death was observed in p533KR induction alone or in ROS activator treatment; whereas the p533KR and ROS group induced substantial cell death, which was rescued by overexpression of SLC7A11 (Figure 5b)[7].

Figure 5. Effects of high levels of ROS on p53-mediated ferroptosis

[7]

a-b: Cell death of Tet-on p53

3KR

cells treated with tetracycline and ROS as control or transfected with SLC7A11-overexpressing plasmid;ALOX12 is essential for the p53-mediated ferroptosis pathway

In a follow-up study, Chu B. et al. reported that ALOX12-mediated, ACSL4-independent ferroptosis pathway is critical for p53-dependent tumor suppression[8]. The ALOX12 gene is located on human chromosome 17p13.1, a labile site for monoallelic deletions in human cancers.

ALOX12 was found to be essential for p53-mediated ferroptosis under ROS stress. ALOX12 depletion had no apparent effect on p53 levels or the expression of its transcriptional targets such as SLC7A11, Mdm2, and p21, but it rescued p53-mediated ferroptosis (Figure 6a-b)[8].

Next, it was found that p53-mediated ferroptosis under ROS stress was regulated independently of GPX4. As shown in Figure 6c, high levels of endogenous lipid peroxidation could be detected in GPX4-knockout cells, whereas lipid peroxidation levels were significantly reduced after ectopic expression of GPX4. At the same time, RSL-3 (GPX4 inhibitor) could abrogate the reducing effect of GPX4 on lipid peroxidation, while the activation of p53 had no effect on it[8].

Then, the effect of ALOX12 on p53-mediated tumor growth inhibition was investigated. Tetracycline-induced p533KR expression significantly reduced tumor cell growth. Moreover, ALOX12 knockdown ablated the tumor suppressive effect of p533KR [Figure 6c-d]. These data suggested that ALOX12 is critical for the tumor cell growth inhibitory activity of p53[8].

Figure 6. The role of ALOX12 in p53-mediated ferroptosis under ROS stress

[8]

a: Western blot analysis of U2OS cells; b: U2OS cell death after treatment with different drugs; c: Changes in cellular lipid peroxidation levels; d: Xenograft tumors in H1299 Tet-on p533KR and ALOX12 knockout mice.iPLA2β is a key regulator of the p53-mediated ferroptosis pathway

In June 2022, Chen Du et al. reporteda mechanism in an article "iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4" in Nature CommunicationsIn this proposed mechanism iPLA2β is a key regulator of p53 activation-induced ferroptosis under high ROS stress conditions and p53 induces ferroptosis in a GPX4-independent manner[9][Figure 7].

Figure 7. Model for the role of ALOX12 and iPLA2β in regulating p53-mediated ferroptosis

[9]

The p53 levels were not affected by ACSL4 and GPX4, in the ACSL4/GPX4 double knockout (ACSL4

-/-

/GPX4

-/-

) human osteosarcoma cell line U2OS. At the same time, p53-mediated transcriptional activation of p21 or repression of SLC7A11 remained unchanged (Fig. 8a). However, when ACSL4

-/-

/GPX4

-/-

cells were exposed to TBH and Nutlin, ferroptosis cell death apparently occurred, which was specifically blocked by ferroptosis inhibitors (Fig. 8b).

Figure 8. p53 mediates ferroptosis in a GPX4-independent manner under ROS stimulation

[9]

a: Effect of Nutlin on p53 protein in U2OS cells; b-d: The effects of cell death influenced by TBH, Nutlin, Ferr-1, Lipro-1, 3-MA, Necrostatin-1, Z-VAD-FMK on WT,ACSL4

-/-

, GPX4

-/-

and U2OS cellsConclusion:The tumor suppressor gene

TP53

is the most studied gene in cancer research. Ferroptosis is a novel form of regulated cell death that has sparked a research frenzy since its discovery. The discovery of connection between p53 and ferroptosis paves a new way for the development of p53-related drugs for cancer treatment.

Related products

Nutlin-3

A potent p53-MDM2 inhibitor with Ki of 90 nM.

Idasanutlin

A potent and selective MDM2 antagonist that inhibits p53-MDM2 binding with IC50 of 6 nM.

Pifithrin-α hydrobromide

A p53 inhibitor that blocks its transcriptional activity and prevents apoptosis; an agonist of aryl hydrocarbon receptor (AhR).

Erastin

A ferroptosis inducer that binds and inhibits voltage-dependent anion channels (VDAC2/VDAC3).

RSL3

An inhibitor of glutathione peroxidase 4 (GPX4) (ferroptosis agonist) that reduces GPX4 expression. .

Ferrostatin-1

A selective ferroptosis inhibitor; antioxidant.

References

[1]. Liz J Hernández Borrero 1, Wafik S El-Deiry, et al. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer. 2021 Aug;1876(1):188556.

[2]. Gaurav Mendiratta, et al. Cancer gene mutation frequencies for the U.S. population. Nat Commun. 2021 Oct 13;12(1):5961

[3]. Elie Dolgin, et al. The most popular genes in the human genome. Nature. 2017 Nov 23;551(7681):427-431.

[4]. Sandra L Harris, et al. The p53 pathway: positive and negative feedback loops. Oncogene. 2005 Apr 18;24(17):2899-908.

[5]. Ou M, et al. Role and mechanism of ferroptosis in neurological diseases. Mol Metab. 2022 Jul;61:101502.

[6]. Y Xie, R Kang, D Tang et al. Ferroptosis: process and function. Cell Death Differ. 2016 Mar;23(3):369-79.

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