AMBRA1

Last updated
AMBRA1
Identifiers
Aliases AMBRA1 , DCAF3, WDR94, autophagy and beclin 1 regulator 1
External IDs OMIM: 611359; MGI: 2443564; HomoloGene: 18204; GeneCards: AMBRA1; OMA:AMBRA1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

55626

228361

Ensembl

ENSG00000110497

ENSMUSG00000040506

UniProt

Q9C0C7

A2AH22

RefSeq (mRNA)

NM_001080754
NM_172669

RefSeq (protein)

NP_001074223
NP_766257

Location (UCSC) Chr 11: 46.4 – 46.59 Mb Chr 2: 91.56 – 91.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

AMBRA1 (activating molecule in Beclin1-regulated autophagy) [5] [6] is a protein that is able to regulate cancer cells through autophagy. [7] AMBRA1 is described as a mechanism cells use to divide [8] and there is new evidence demonstrating the role and impact of AMBRA1 as a candidate for the treatment of several disorders and diseases, including anticancer therapy. It is known to suppress tumors [9] and plays a role in mitophagy and apoptosis. [10] AMBRA1 can be found in the cytoskeleton and mitochondria and during the process of autophagy, it is localized at the endoplasmic reticulum. [11] In normal conditions, AMBRA1 is dormant and will bind to BCL2 in the outer membrane. This relocation enables autophagosome nucleation. [12] AMBRA1 protein is involved in several cellular processes and is involved in the regulation of the immune system and nervous system. [6]

Function

AMBRA1 serves to regulate the process of autophagy and this is the cellular breakdown and recycling of unnecessary or damaged cellular components. [10] This protein interacts with other proteins and genes to initiate the formation of autophagosomes, an essential component of autophagy. Cellular processes such as cell proliferation, apoptosis, and cellular metabolism are regulated through the interactions between AMBRA1 and other proteins. [9] AMBRA1 is involved in regulating the cell cycle and it recognizes and binds to D-type cyclins which promotes cell proliferation. [13] This leads to cyclin-D degradation where AMBRA1 suppresses tumors, prevents their growth, and promotes genetic integrity. [12] AMBRA1 is also known to mediate polyubiquitylation of several proteins. [12] Bartolomeo et al. demonstrated AMBRA1 signals the motor complex to initiate autophagy when it is released from microtubules. [13] Through autophagy, cellular homeostasis is maintained, and the buildup of toxic or damaged proteins is prevented. Reynolds(2021) shows the repercussions of the loss of AMBRA1, which can no longer control the cell cycle from uncontrolled cell division and growth. [7] One of the interactions AMBRA1 has with Beclin1 aids in cell proliferation and protein replacement during neural development. [14] AMBRA1 is able to promote activity in PIK3C3, increase kinase activity during autophagy, and activate ULK1. [9] AMBRA1 promotes FOXO3 and Nazio et al. (2021) showed when AMBRA1 is reduced, there is inhibition of STAT3 signaling which reduces the regulation of innate and adaptive immunity. [12] In addition, AMBRA1 is an essential component for STAT3 signaling as FOXO3 regulates gene expression in autophagy. [12]

Mechanism

The exact mechanisms of this protein are not yet fully understood. Several processes including autophagy and apoptosis are some that AMBRA1 is involved with. [10] Through the formation of autophagosomes, structures that engulf cellular components to break them down, [15] autophagy is initiated. AMBRA1 regulates the activity of the mTORC1 complex and this complex serves as a regulator of cell metabolism and growth. [10] Apart from autophagy, AMBRA1 plays an essential role in apoptosis and cell proliferation. For enabling cell death, the p53 pathway is activated and this is done upon the release of cytochrome C from mitochondria. [16] AMBRA1 has been a topic of research for anti-cancer therapies through the regulation of the immune system. [10] AMBRA1 is additionally involved in the development of the nervous system through the regulation of biological processes involving Parkinson's disease and other neurodegenerative disorders. [9]

Interactions

Simoneschi et al. [13] demonstrated that there is an interaction between AMBRA1 and the cyclin-D pathway. D-type cyclins activate CDK4 and CDK6 and AMBRA1 protein targets these cyclins for degradation. The decrease in AMBRA1 proteins showed the prevention of polyubiquitylation of cyclin D1. [13] The interactions provide evidence that AMBRA1 plays a role in the regulation of different cellular processes such as autophagy, cell proliferation, apoptosis, and metabolism. AMBRA1 interacts with Beclin1 and ULK1 to initiate autophagy and form autophagosomes. [14] The interaction with ULK1 also regulates cell proliferation. [14] AMBRA1 interacts with Bcl2 and mito-and this aids in regulating and promoting apoptosis. [17] There is a correlation between apoptosis and autophagy where AMBRA1 is released from Bcl2 when autophagy takes place. [14] This process increases Beclin1 activity and Strappazzon et al. found that the interactions are reduced during apoptosis. [14] When AMBRA1 interacts with DLC1, a complex associated with cell division, the complex is moved to the endoplasmic reticulum [13] and the complex is harnessed to the cytoskeleton. [10] AMBRA1 also interacts with the protein phosphatase 2A (PPP2CA) and this promotes MYC dephosphorylation and degradation. [9] MYC is an oncogene and when degraded, it results in tumor suppression. [18] The interactions with AMBRA1 and other proteins suggest the importance of AMBRA1 in cellular processes.

Clinical significance

AMBRA1 is clinically significant due to the importance of this protein in cellular processes such as apoptosis and cell proliferation. Diseases such as cancer, [10] [13] neurodegenerative disorders and autoimmune diseases can arise. Frias et al., through studies concluded that the deletion of AMBRA1 results in the inhibition of tumors and melanoma and reduced cytokine-mediated signaling. [19] Tumorigenisis and tumor proliferation takes place when AMBRA1 fails to interact and promote the degradation of cyclin D. [10] Diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease contain autophagy alterations. [20] AMBRA1 plays a role in the development of Parkinson's disease and in interacting with Parkin, an E3 ubiquitin ligase, there is inhibition of Parkin mitophagy. [19] AMBRA1 is involved in the regulation of the immune system and upcoming research demonstrates this protein might play a role in the development of autoimmune diseases since AMBRA1 is involved in autophagy. [14] Understanding the functions of AMBRA1 and the role it plays in disease pathogenesis provide insight into the development of new treatment and therapies for the listed disorders.

Related Research Articles

Cell biology is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and functioning of organisms. Cell biology is the study of the structural and functional units of cells. Cell biology encompasses both prokaryotic and eukaryotic cells and has many subtopics which may include the study of cell metabolism, cell communication, cell cycle, biochemistry, and cell composition. The study of cells is performed using several microscopy techniques, cell culture, and cell fractionation. These have allowed for and are currently being used for discoveries and research pertaining to how cells function, ultimately giving insight into understanding larger organisms. Knowing the components of cells and how cells work is fundamental to all biological sciences while also being essential for research in biomedical fields such as cancer, and other diseases. Research in cell biology is interconnected to other fields such as genetics, molecular genetics, molecular biology, medical microbiology, immunology, and cytochemistry.

<span class="mw-page-title-main">Autophagy</span> Process of cells digesting parts of themselves

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">HSPA8</span> Protein-coding gene in the species Homo sapiens

Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.

<span class="mw-page-title-main">Bafilomycin</span> Chemical compound

The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.

p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

<span class="mw-page-title-main">YWHAZ</span> Protein-coding gene in the species Homo sapiens

14-3-3 protein zeta/delta (14-3-3ζ) is a protein that in humans is encoded by the YWHAZ gene on chromosome 8. The protein encoded by this gene is a member of the 14-3-3 protein family and a central hub protein for many signal transduction pathways. 14-3-3ζ is a major regulator of apoptotic pathways critical to cell survival and plays a key role in a number of cancers and neurodegenerative diseases.

<span class="mw-page-title-main">BNIP3</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene.

<span class="mw-page-title-main">CD47</span> Protein-coding gene in humans

CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.

<span class="mw-page-title-main">TANK-binding kinase 1</span> Protein-coding gene in the species Homo sapiens

TBK1 is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase. It is encoded by the TBK1 gene in humans. This kinase is mainly known for its role in innate immunity antiviral response. However, TBK1 also regulates cell proliferation, apoptosis, autophagy, and anti-tumor immunity. Insufficient regulation of TBK1 activity leads to autoimmune, neurodegenerative diseases or tumorigenesis.

<span class="mw-page-title-main">ULK1</span> Enzyme found in humans

ULK1 is an enzyme that in humans is encoded by the ULK1 gene.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

<span class="mw-page-title-main">ATG8</span> Protein in budding yeast

Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals, this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.

AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in S.cerevisiae, encoded by the gene ATG1. It is essential for the initial building of the autophagosome and Cvt vesicles. In a non-kinase role it is - through complex formation with Atg13 and Atg17 - directly controlled by the TOR kinase, a sensor for nutrient availability.

<span class="mw-page-title-main">Retinoblastoma protein</span> Mammalian protein found in humans

The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.

Nix is a pro-apoptotic gene that is regulated by Histotoxic hypoxia. It expresses a signaling protein related to the BH3-only family. This protein induces autophagy, an intracellular function by which cytoplasmic components are delivered to the lysosome to be broken down and used elsewhere or excreted from the cell. This protein is important in development because it allows cells to have a consistent store of cellular components. It also holds an important role in the differentiation and maturation of erythrocytes and lymphocytes by the process of mitophagy with the help of its regulator BNIP3. Using a gene knockout technique in mice, scientists have been able to attribute this pruning of mitochondria and induction of cellular necrosis to the expression of the Nix gene. The Nix protein may be associated with certain kinds of cancer formation. In mouse models, loss of Nix resulted in a delayed onset of tumors for pancreatic cancer, and was additionally associated with reduced mitophagy and increased oxidative metabolism. Nix therefore may be a tumor promoter for pancreatic cancer.

<span class="mw-page-title-main">Mitochondria associated membranes</span> Cellular structure

Mitochondria-associated membranes (MAMs) represent regions of the endoplasmic reticulum (ER) which are reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.

<span class="mw-page-title-main">Rubicon (protein)</span> Human protein involved in autophagy regulation

Rubicon is a protein that in humans is encoded by the RUBCN gene. Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components. Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7, and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000110497 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040506 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Schoenherr C, Byron A, Griffith B, Loftus A, Wills JC, Munro AF, et al. (August 2020). "The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes". The Journal of Biological Chemistry. 295 (34): 12045–12057. doi: 10.1074/jbc.ra120.012565 . PMC   7443501 . PMID   32616651.
  6. 1 2 Nazio F, Po A, Abballe L, Ballabio C, Diomedi Camassei F, Bordi M, et al. (September 2021). "Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling". Acta Neuropathologica. 142 (3): 537–564. doi:10.1007/s00401-021-02347-7. PMC   8357694 . PMID   34302498.
  7. 1 2 Li X, Lyu Y, Li J, Wang X (2022). "AMBRA1 and its role as a target for anticancer therapy". Frontiers in Oncology. 12: 946086. doi: 10.3389/fonc.2022.946086 . PMC   9551033 . PMID   36237336.
  8. ↑ "AMBRA1 Protein Found to Be an Important Tumor Suppressor - NCI". www.cancer.gov. 2021-05-14. Retrieved 2023-05-09.
  9. 1 2 3 4 5 "AMBRA1 Protein Found to Be an Important Tumor Suppressor". NCI. 14 May 2021.
  10. 1 2 3 4 5 6 7 8 Schoenherr C, Byron A, Griffith B, Loftus A, Wills JC, Munro AF, et al. (August 2020). "The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes". The Journal of Biological Chemistry. 295 (34): 12045–12057. doi: 10.1074/jbc.RA120.012565 . PMC   7443501 . PMID   32616651.
  11. ↑ "UniProt". www.uniprot.org. Retrieved 2023-05-09.
  12. 1 2 3 4 5 "AMRA1_HUMAN". UniProt. Q9C0C7.
  13. 1 2 3 4 5 6 Simoneschi D, Rona G, Zhou N, Jeong YT, Jiang S, Milletti G, et al. (April 2021). "CRL4AMBRA1 is a master regulator of D-type cyclins". Nature. 592 (7856): 789–793. Bibcode:2021Natur.592..789S. doi:10.1038/s41586-021-03445-y. PMC   8875297 . PMID   33854235.
  14. 1 2 3 4 5 6 Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, et al. (October 2010). "The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy". The Journal of Cell Biology. 191 (1): 155–168. doi:10.1083/jcb.201002100. PMC   2953445 . PMID   20921139.
  15. ↑ "Autophagosome", Wikipedia, 2022-11-14, retrieved 2023-05-10
  16. ↑ Strappazzon F, Di Rita A, Cianfanelli V, D'Orazio M, Nazio F, Fimia GM, Cecconi F (June 2016). "Prosurvival AMBRA1 turns into a proapoptotic BH3-like protein during mitochondrial apoptosis". Autophagy. 12 (6): 963–975. doi:10.1080/15548627.2016.1164359. PMC   4922440 . PMID   27123694.
  17. ↑ Strappazzon F, Vietri-Rudan M, Campello S, Nazio F, Florenzano F, Fimia GM, et al. (April 2011). "Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy". The EMBO Journal. 30 (7): 1195–1208. doi:10.1038/emboj.2011.49. PMC   3094111 . PMID   21358617.
  18. ↑ Dingar D, Tu WB, Resetca D, Lourenco C, Tamachi A, De Melo J, et al. (August 2018). "MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability". Nature Communications. 9 (1): 3502. Bibcode:2018NatCo...9.3502D. doi:10.1038/s41467-018-05660-0. PMC   6115416 . PMID   30158517.
  19. 1 2 Frias A, Di Leo L, Antoranz A, Nazerai L, Carretta M, Bodemeyer V, et al. (March 2023). "Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma". Journal for Immunotherapy of Cancer. 11 (3): e006389. doi:10.1136/jitc-2022-006389. PMC   9990656 . PMID   36868570.
  20. ↑ Van Humbeeck C, Cornelissen T, Hofkens H, Mandemakers W, Gevaert K, De Strooper B, Vandenberghe W (July 2011). "Parkin interacts with Ambra1 to induce mitophagy". The Journal of Neuroscience. 31 (28): 10249–10261. doi:10.1523/JNEUROSCI.1917-11.2011. PMC   6623066 . PMID   21753002.
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