AIFM2: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''Apoptosis-inducing factor 2''' (AIFM2), also known as apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a [[protein]] that in humans is encoded by the ''AIFM2'' [[gene]], also known as p53-responsive gene 3 (PRG3), on chromosome 10.<ref name="pmid12135761">{{cite journal |vauthors=Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N | title = A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF) | journal = FEBS Lett | volume = 524 | issue = 1-3 | pages = 163–71 |date=Jul 2002 | pmid = 12135761 | pmc =  | doi =10.1016/S0014-5793(02)03049-1 }}</ref><ref name="pmid11980907">{{cite journal |vauthors=Wu M, Xu LG, Li X, Zhai Z, Shu HB | title = AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis | journal = J Biol Chem | volume = 277 | issue = 28 | pages = 25617–23 |date=Jul 2002 | pmid = 11980907 | pmc =  | doi = 10.1074/jbc.M202285200 }}</ref><ref name="pmid15958387">{{cite journal |vauthors=Marshall KR, Gong M, Wodke L, Lamb JH, Jones DJ, Farmer PB, Scrutton NS, Munro AW | title = The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity | journal = J Biol Chem | volume = 280 | issue = 35 | pages = 30735–40 |date=Aug 2005 | pmid = 15958387 | pmc =  | doi = 10.1074/jbc.M414018200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=84883| accessdate = }}</ref>
'''Apoptosis-inducing factor 2''' (AIFM2), also known as apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a [[protein]] that in humans is encoded by the ''AIFM2'' [[gene]], also known as p53-responsive gene 3 (PRG3), on chromosome 10.<ref name="pmid12135761">{{cite journal | vauthors = Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N | title = A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF) | journal = FEBS Letters | volume = 524 | issue = 1-3 | pages = 163–71 | date = July 2002 | pmid = 12135761 | pmc =  | doi = 10.1016/S0014-5793(02)03049-1 }}</ref><ref name="pmid11980907">{{cite journal | vauthors = Wu M, Xu LG, Li X, Zhai Z, Shu HB | title = AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis | journal = The Journal of Biological Chemistry | volume = 277 | issue = 28 | pages = 25617–23 | date = July 2002 | pmid = 11980907 | pmc =  | doi = 10.1074/jbc.M202285200 }}</ref><ref name="pmid15958387">{{cite journal | vauthors = Marshall KR, Gong M, Wodke L, Lamb JH, Jones DJ, Farmer PB, Scrutton NS, Munro AW | title = The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity | journal = The Journal of Biological Chemistry | volume = 280 | issue = 35 | pages = 30735–40 | date = September 2005 | pmid = 15958387 | pmc =  | doi = 10.1074/jbc.M414018200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=84883| access-date = }}</ref>


This gene encodes a [[flavoprotein]] [[oxidoreductase]] that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.<ref name="entrez"/><ref name=pmid17711848>{{cite journal|last1=Gong|first1=M|last2=Hay|first2=S|last3=Marshall|first3=KR|last4=Munro|first4=AW|last5=Scrutton|first5=NS|title=DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis.|journal=The Journal of Biological Chemistry|date=12 October 2007|volume=282|issue=41|pages=30331–40|pmid=17711848|doi=10.1074/jbc.m703713200}}</ref>
This gene encodes a [[flavoprotein]] [[oxidoreductase]] that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.<ref name="entrez"/><ref name=pmid17711848>{{cite journal | vauthors = Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS | title = DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 30331–40 | date = October 2007 | pmid = 17711848 | doi = 10.1074/jbc.m703713200 }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
| section_title =  
| summary_text = The protein encoded by this gene has significant [[Homology (biology)|homology]] to [[NADH]] [[oxidoreductase]]s and the [[apoptosis-inducing factor]] PDCD8/[[Apoptosis-inducing factor|AIF]]. [[Overexpression]] of this gene has been shown to induce [[apoptosis]]. The expression of this gene is found to be induced by [[tumor suppressor protein]] [[p53]] in [[colon cancer]] cells.<ref name="entrez"/>
}}


==Structure==
The protein encoded by this gene has significant [[Homology (biology)|homology]] to [[NADH]] [[oxidoreductase]]s and the [[apoptosis-inducing factor]] PDCD8/[[Apoptosis-inducing factor|AIF]]. [[Overexpression]] of this gene has been shown to induce [[apoptosis]]. The expression of this gene is found to be induced by [[tumor suppressor protein]] [[p53]] in [[colon cancer]] cells.<ref name="entrez"/>


AIFM2 can be found only in other [[eukaryote]]s, but it shares significant sequence [[homology (biology)|homology]] with [[Apoptosis-inducing factor|AIF]] and NADH oxidoreductases across both [[prokaryote]]s and eukaryotes.<ref name="pmid11980907"/><ref name="pmid15958387"/><ref name=pmid15273740>{{cite journal|last1=Wu|first1=M|last2=Xu|first2=LG|last3=Su|first3=T|last4=Tian|first4=Y|last5=Zhai|first5=Z|last6=Shu|first6=HB|title=AMID is a p53-inducible gene downregulated in tumors.|journal=Oncogene|date=2 September 2004|volume=23|issue=40|pages=6815–9|pmid=15273740|doi=10.1038/sj.onc.1207909}}</ref> Sequence analysis reveals that the ''AIFM2'' [[gene promoter]] contains a consensus [[transcription (genetics)|transcription]] initiator sequence instead of a [[TATA box]].<ref name=pmid15273740/> Though AIFM2 also lacks a recognizable [[targeting sequence|mitochondrial localization sequence]] and cannot enter the mitochondria, it is found to adhere to the [[outer mitochondrial membrane]] (OMM), where it forms a ring-like structure.<ref name="pmid11980907"/><ref name=pmid12135761/><ref name="pmid15958387"/><ref name=pmid15273740/><ref name=pmid17711848/> Two deletion mutations at the [[C-terminal]] (aa 1–185 and 1–300) result in [[Cell nucleus|nuclear]] localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction.<ref name="pmid11980907"/> Meanwhile, mutations in the [[N-terminal]] putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently.<ref name="pmid15958387"/><ref name=pmid12135761 /> It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.<ref name="pmid15958387"/>
== Structure ==
 
AIFM2 can be found only both in [[prokaryote]]s and eukaryotes.<ref name="pmid11980907"/><ref name="pmid15958387"/><ref name="Klim 2121–2134">{{cite journal | vauthors = Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S | title = Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes | journal = G3 | volume = 8 | issue = 6 | pages = 2121–2134 | date = May 2018 | pmid = 29703784 | pmc = 5982838 | doi = 10.1534/g3.118.200295 }}</ref><ref name=pmid15273740>{{cite journal | vauthors = Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB | title = AMID is a p53-inducible gene downregulated in tumors | journal = Oncogene | volume = 23 | issue = 40 | pages = 6815–9 | date = September 2004 | pmid = 15273740 | doi = 10.1038/sj.onc.1207909 }}</ref> Sequence analysis reveals that the ''AIFM2'' [[gene promoter]] contains a consensus [[transcription (genetics)|transcription]] initiator sequence instead of a [[TATA box]].<ref name=pmid15273740/> Though AIFM2 also lacks a recognizable [[targeting sequence|mitochondrial localization sequence]] and cannot enter the mitochondria, it is found to adhere to the [[outer mitochondrial membrane]] (OMM), where it forms a ring-like structure.<ref name="pmid11980907"/><ref name=pmid12135761/><ref name="pmid15958387"/><ref name=pmid15273740/><ref name=pmid17711848/> Two deletion mutations at the [[C-terminal]] (aa 1–185 and 1–300) result in [[Cell nucleus|nuclear]] localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction.<ref name="pmid11980907"/> Meanwhile, mutations in the [[N-terminal]] putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently.<ref name="pmid15958387"/><ref name=pmid12135761 /> It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.<ref name="pmid15958387"/>


The ''AIFM2'' gene contains a putative p53-binding element in [[intron]] 5, suggesting that its gene expression can be activated by p53.<ref name=pmid12135761/><ref name="pmid15958387"/><ref name=pmid15273740/>
The ''AIFM2'' gene contains a putative p53-binding element in [[intron]] 5, suggesting that its gene expression can be activated by p53.<ref name=pmid12135761/><ref name="pmid15958387"/><ref name=pmid15273740/>


==Function==
== Function ==


This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces [[caspase]]- and [[p53]]-independent apoptosis.<ref name="pmid11980907"/><ref name=pmid12135761/><ref name="pmid15958387"/> The exact mechanisms remain unknown, but AIFM2 is found to [[subcellular localization|localize]] to the [[cytosol]] and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors.<ref name="pmid11980907"/> Also, under conditions of stress which activate p53-mediated apoptosis, such as [[hypoxia (medical)|hypoxia]], AIMF2 may stabilize [[p53]] by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the ''AIMF2'' gene is highly expressed in the [[heart]], followed by [[liver]] and [[skeletal muscle]], with low levels detected in the [[placenta]], [[lung]], [[kidney]], and [[pancreas]] and the lowest in the [[brain]]. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function.<ref name=pmid12135761/> For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF.<ref name="pmid15958387"/> Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism.<ref name=pmid12135761/> Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating [[reactive oxygen species]] (ROS) to maintain survival signaling.<ref name=pmid17711848/>
This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces [[caspase]]- and [[p53]]-independent apoptosis.<ref name="pmid11980907"/><ref name=pmid12135761/><ref name="pmid15958387"/> The exact mechanisms remain unknown, but AIFM2 is found to [[subcellular localization|localize]] to the [[cytosol]] and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors.<ref name="pmid11980907"/> Also, under conditions of stress which activate p53-mediated apoptosis, such as [[hypoxia (medical)|hypoxia]], AIMF2 may stabilize [[p53]] by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the ''AIMF2'' gene is highly expressed in the [[heart]], followed by [[liver]] and [[skeletal muscle]], with low levels detected in the [[placenta]], [[lung]], [[kidney]], and [[pancreas]] and the lowest in the [[brain]]. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function.<ref name=pmid12135761/> For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF.<ref name="pmid15958387"/> Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism.<ref name=pmid12135761/> Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating [[reactive oxygen species]] (ROS) to maintain survival signaling.<ref name=pmid17711848/>


==Clinical Significance==
==Clinical significance==


''AIFM2'' has been implicated in [[tumorigenesis]] as a p53-inducible gene.<ref name=pmid15273740/> ''AIFM2'' mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that ''AIFM2'' mRNA transcripts were only detected in [[colon cancer]] and [[B-cell lymphoma]] cell lines.<ref name="pmid11980907"/><ref name="pmid15958387"/> Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.<ref name=pmid15273740/>
''AIFM2'' has been implicated in [[tumorigenesis]] as a p53-inducible gene.<ref name=pmid15273740/> ''AIFM2'' mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that ''AIFM2'' mRNA transcripts were only detected in [[colon cancer]] and [[B-cell lymphoma]] cell lines.<ref name="pmid11980907"/><ref name="pmid15958387"/> Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.<ref name=pmid15273740/>


==Interactions==
== Evolution ==
The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.<ref name="Klim 2121–2134"/>
 
== Interactions ==
 
AIFM2 is shown to [[protein interaction|interact]] with [[p53]].<ref name=pmid12135761/>
AIFM2 is shown to [[protein interaction|interact]] with [[p53]].<ref name=pmid12135761/>


Line 36: Line 38:
*[[pyridine nucleotide coenzyme]].<ref name="pmid15958387"/>
*[[pyridine nucleotide coenzyme]].<ref name="pmid15958387"/>


==References==
== References ==
{{reflist}}
{{reflist}}


==External links==
== External links ==
* {{UCSC gene info|AIFM2}}
* {{UCSC gene info|AIFM2}}
* {{UCSC gene info|PRG3}}
* {{UCSC gene info|PRG3}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Horikoshi N, Cong J, Kley N, Shenk T | title = Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene | journal = Biochemical and Biophysical Research Communications | volume = 261 | issue = 3 | pages = 864–9 | date = August 1999 | pmid = 10441517 | doi = 10.1006/bbrc.1999.1123 }}
| citations =
* {{cite journal | vauthors = Zhang W, Li D, Mehta JL | title = Role of AIF in human coronary artery endothelial cell apoptosis | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 286 | issue = 1 | pages = H354-8 | date = January 2004 | pmid = 14684364 | doi = 10.1152/ajpheart.00579.2003 }}
*{{cite journal |vauthors=Horikoshi N, Cong J, Kley N, Shenk T |title=Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene. |journal=Biochem. Biophys. Res. Commun. |volume=261 |issue= 3 |pages= 864–9 |year= 1999 |pmid= 10441517 |doi= 10.1006/bbrc.1999.1123 }}
* {{cite journal | vauthors = Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB | title = AMID is a p53-inducible gene downregulated in tumors | journal = Oncogene | volume = 23 | issue = 40 | pages = 6815–9 | date = September 2004 | pmid = 15273740 | doi = 10.1038/sj.onc.1207909 }}
*{{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 |display-authors=etal}}
* {{cite journal | vauthors = Varecha M, Amrichová J, Zimmermann M, Ulman V, Lukásová E, Kozubek M | title = Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells | journal = Apoptosis | volume = 12 | issue = 7 | pages = 1155–71 | date = July 2007 | pmid = 17347867 | doi = 10.1007/s10495-007-0061-0 }}
*{{cite journal  |vauthors=Zhang W, Li D, Mehta JL |title=Role of AIF in human coronary artery endothelial cell apoptosis. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=286 |issue= 1 |pages= H354–8 |year= 2004 |pmid= 14684364 |doi= 10.1152/ajpheart.00579.2003 }}
* {{cite journal | vauthors = Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS | title = DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 30331–40 | date = October 2007 | pmid = 17711848 | doi = 10.1074/jbc.M703713200 }}
*{{cite journal |vauthors=Ota T, Suzuki Y, Nishikawa T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |display-authors=etal}}
*{{cite journal  |vauthors=Deloukas P, Earthrowl ME, Grafham DV |title=The DNA sequence and comparative analysis of human chromosome 10. |journal=Nature |volume=429 |issue= 6990 |pages= 375–81 |year= 2004 |pmid= 15164054 |doi= 10.1038/nature02462 |display-authors=etal}}
*{{cite journal  |vauthors=Wu M, Xu LG, Su T |title=AMID is a p53-inducible gene downregulated in tumors. |journal=Oncogene |volume=23 |issue= 40 |pages= 6815–9 |year= 2004 |pmid= 15273740 |doi= 10.1038/sj.onc.1207909 |display-authors=etal}}
*{{cite journal |vauthors=Gerhard DS, Wagner L, Feingold EA |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 |display-authors=etal}}
*{{cite journal  |vauthors=Varecha M, Amrichová J, Zimmermann M |title=Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells. |journal=Apoptosis |volume=12 |issue= 7 |pages= 1155–71 |year= 2007 |pmid= 17347867 |doi= 10.1007/s10495-007-0061-0 |display-authors=etal}}
*{{cite journal |vauthors=Gong M, Hay S, Marshall KR |title=DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis. |journal=J. Biol. Chem. |volume=282 |issue= 41 |pages= 30331–40 |year= 2007 |pmid= 17711848 |doi= 10.1074/jbc.M703713200 |display-authors=etal}}
}}
{{refend}}
{{refend}}


{{Portal|Mitochondria}}
{{Portal|Mitochondria}}


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[[Category:Proteins]]
[[Category:Proteins]]

Latest revision as of 05:57, 3 August 2018

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SpeciesHumanMouse
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Apoptosis-inducing factor 2 (AIFM2), also known as apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.[1][2][3][4]

This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.[4][5]

Function

The protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Overexpression of this gene has been shown to induce apoptosis. The expression of this gene is found to be induced by tumor suppressor protein p53 in colon cancer cells.[4]

Structure

AIFM2 can be found only both in prokaryotes and eukaryotes.[2][3][6][7] Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box.[7] Though AIFM2 also lacks a recognizable mitochondrial localization sequence and cannot enter the mitochondria, it is found to adhere to the outer mitochondrial membrane (OMM), where it forms a ring-like structure.[2][1][3][7][5] Two deletion mutations at the C-terminal (aa 1–185 and 1–300) result in nuclear localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction.[2] Meanwhile, mutations in the N-terminal putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently.[3][1] It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.[3]

The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.[1][3][7]

Function

This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent apoptosis.[2][1][3] The exact mechanisms remain unknown, but AIFM2 is found to localize to the cytosol and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors.[2] Also, under conditions of stress which activate p53-mediated apoptosis, such as hypoxia, AIMF2 may stabilize p53 by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the AIMF2 gene is highly expressed in the heart, followed by liver and skeletal muscle, with low levels detected in the placenta, lung, kidney, and pancreas and the lowest in the brain. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function.[1] For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF.[3] Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism.[1] Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating reactive oxygen species (ROS) to maintain survival signaling.[5]

Clinical significance

AIFM2 has been implicated in tumorigenesis as a p53-inducible gene.[7] AIFM2 mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that AIFM2 mRNA transcripts were only detected in colon cancer and B-cell lymphoma cell lines.[2][3] Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.[7]

Evolution

The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.[6]

Interactions

AIFM2 is shown to interact with p53.[1]

AIFM2 is not inhibited by Bcl-2.[1]

AIFM2 can also bind the following coenzymes:

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N (July 2002). "A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF)". FEBS Letters. 524 (1–3): 163–71. doi:10.1016/S0014-5793(02)03049-1. PMID 12135761.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Wu M, Xu LG, Li X, Zhai Z, Shu HB (July 2002). "AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis". The Journal of Biological Chemistry. 277 (28): 25617–23. doi:10.1074/jbc.M202285200. PMID 11980907.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Marshall KR, Gong M, Wodke L, Lamb JH, Jones DJ, Farmer PB, Scrutton NS, Munro AW (September 2005). "The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity". The Journal of Biological Chemistry. 280 (35): 30735–40. doi:10.1074/jbc.M414018200. PMID 15958387.
  4. ↑ 4.0 4.1 4.2 "Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2".
  5. ↑ 5.0 5.1 5.2 Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS (October 2007). "DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis". The Journal of Biological Chemistry. 282 (41): 30331–40. doi:10.1074/jbc.m703713200. PMID 17711848.
  6. ↑ 6.0 6.1 Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S (May 2018). "Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes". G3. 8 (6): 2121–2134. doi:10.1534/g3.118.200295. PMC 5982838. PMID 29703784.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB (September 2004). "AMID is a p53-inducible gene downregulated in tumors". Oncogene. 23 (40): 6815–9. doi:10.1038/sj.onc.1207909. PMID 15273740.

External links

Further reading

  • Horikoshi N, Cong J, Kley N, Shenk T (August 1999). "Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene". Biochemical and Biophysical Research Communications. 261 (3): 864–9. doi:10.1006/bbrc.1999.1123. PMID 10441517.
  • Zhang W, Li D, Mehta JL (January 2004). "Role of AIF in human coronary artery endothelial cell apoptosis". American Journal of Physiology. Heart and Circulatory Physiology. 286 (1): H354–8. doi:10.1152/ajpheart.00579.2003. PMID 14684364.
  • Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB (September 2004). "AMID is a p53-inducible gene downregulated in tumors". Oncogene. 23 (40): 6815–9. doi:10.1038/sj.onc.1207909. PMID 15273740.
  • Varecha M, Amrichová J, Zimmermann M, Ulman V, Lukásová E, Kozubek M (July 2007). "Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells". Apoptosis. 12 (7): 1155–71. doi:10.1007/s10495-007-0061-0. PMID 17347867.
  • Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS (October 2007). "DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis". The Journal of Biological Chemistry. 282 (41): 30331–40. doi:10.1074/jbc.M703713200. PMID 17711848.
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