BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis
B NIP2 and Cdc42GAP homology ( B CH) m otif- c ontaining molecule at the c arboxyl-terminal region 1 ( BMCC1 ) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple c...
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| creator | Tatsumi, Y Takano, R Islam, M S Yokochi, T Itami, M Nakamura, Y Nakagawara, A |
| description | B
NIP2 and Cdc42GAP homology (
B
CH)
m
otif-
c
ontaining molecule at the
c
arboxyl-terminal region
1
(
BMCC1
) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis. |
| doi_str_mv | 10.1038/cddis.2014.568 |
| format | Article |
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NIP2 and Cdc42GAP homology (
B
CH)
m
otif-
c
ontaining molecule at the
c
arboxyl-terminal region
1
(
BMCC1
) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/cddis.2014.568</identifier><identifier>PMID: 25611382</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 14/105 ; 14/19 ; 631/337 ; 631/80/82/23 ; 631/80/86 ; 692/699/67/2332 ; 82/51 ; 82/80 ; 96 ; Antibodies ; Apoptosis ; Apoptosis Regulatory Proteins - metabolism ; Bcl-2-Like Protein 11 ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Culture ; Cell Line, Tumor ; Cisplatin - pharmacology ; DNA Damage ; Down-Regulation - drug effects ; Epithelium - drug effects ; Epithelium - metabolism ; Forkhead Box Protein O3 ; Forkhead Transcription Factors - metabolism ; Gene Knockdown Techniques ; Humans ; Immunology ; Life Sciences ; Membrane Proteins - metabolism ; Neoplasm Proteins - metabolism ; Neuroblastoma - enzymology ; Neuroblastoma - pathology ; Original ; original-article ; Phosphorylation - drug effects ; Phosphothreonine - metabolism ; Protein Binding - drug effects ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; RNA, Small Interfering - metabolism ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology</subject><ispartof>Cell death & disease, 2015-01, Vol.6 (1), p.e1607-e1607</ispartof><rights>The Author(s) 2015</rights><rights>Copyright Nature Publishing Group Jan 2015</rights><rights>Copyright © 2015 Macmillan Publishers Limited 2015 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-7e2741be4b96cdfc8c35c13386d8185d26f511ab67a15444dde9159df3a1c6d3</citedby><cites>FETCH-LOGICAL-c557t-7e2741be4b96cdfc8c35c13386d8185d26f511ab67a15444dde9159df3a1c6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669766/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669766/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,27907,27908,41103,42172,51559,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25611382$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tatsumi, Y</creatorcontrib><creatorcontrib>Takano, R</creatorcontrib><creatorcontrib>Islam, M S</creatorcontrib><creatorcontrib>Yokochi, T</creatorcontrib><creatorcontrib>Itami, M</creatorcontrib><creatorcontrib>Nakamura, Y</creatorcontrib><creatorcontrib>Nakagawara, A</creatorcontrib><title>BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>B
NIP2 and Cdc42GAP homology (
B
CH)
m
otif-
c
ontaining molecule at the
c
arboxyl-terminal region
1
(
BMCC1
) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis.</description><subject>13/2</subject><subject>14/105</subject><subject>14/19</subject><subject>631/337</subject><subject>631/80/82/23</subject><subject>631/80/86</subject><subject>692/699/67/2332</subject><subject>82/51</subject><subject>82/80</subject><subject>96</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Bcl-2-Like Protein 11</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Line, Tumor</subject><subject>Cisplatin - pharmacology</subject><subject>DNA Damage</subject><subject>Down-Regulation - drug effects</subject><subject>Epithelium - drug effects</subject><subject>Epithelium - metabolism</subject><subject>Forkhead Box Protein O3</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Immunology</subject><subject>Life Sciences</subject><subject>Membrane Proteins - metabolism</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Neuroblastoma - enzymology</subject><subject>Neuroblastoma - pathology</subject><subject>Original</subject><subject>original-article</subject><subject>Phosphorylation - drug effects</subject><subject>Phosphothreonine - metabolism</subject><subject>Protein Binding - drug effects</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkc1rHCEYh4fS0oQ01x6L0EsP2Y3fo5dCMvSLbOhl7-Kos2vY1ak6Cfvf1-2mYVsC8aDC-_i86q9p3iM4R5CIS2Otz3MMEZ0zLl41pxhSNKNCyNdH-5PmPOc7WAchEDP-tjmpM0JE4NNGX992HboAD2tv1sBnoAPwobikTfFhBUadSnAJxAFcdwt8AXQpLky6uAyubpZgj937sqsFY-J21ME7C_od0GMcS8w-v2veDHqT3fnjetYsv35Zdt9ni5_ffnRXi5lhrC2z1uGWot7RXnJjByMMYQYRIrgVSDCL-cAQ0j1vNWKUUmudREzagWhkuCVnzeeDdpz6rbPGhZL0Ro3Jb3Xaqai9-rcS_Fqt4r2inMuW8yr49ChI8dfkclFbn43bbHRwccoKtRLKFjIqX0Y5w0RSzvbWj_-hd3FKoX5EFQomsaypVGp-oEyKOSc3PN0bQbWPWv2JWu2jVjXqeuDD8Wuf8L_BVuDyAORaCiuXjvo-r_wNFFuzzQ</recordid><startdate>20150101</startdate><enddate>20150101</enddate><creator>Tatsumi, Y</creator><creator>Takano, R</creator><creator>Islam, M S</creator><creator>Yokochi, T</creator><creator>Itami, M</creator><creator>Nakamura, Y</creator><creator>Nakagawara, A</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20150101</creationdate><title>BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis</title><author>Tatsumi, Y ; Takano, R ; Islam, M S ; Yokochi, T ; Itami, M ; Nakamura, Y ; Nakagawara, A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-7e2741be4b96cdfc8c35c13386d8185d26f511ab67a15444dde9159df3a1c6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13/2</topic><topic>14/105</topic><topic>14/19</topic><topic>631/337</topic><topic>631/80/82/23</topic><topic>631/80/86</topic><topic>692/699/67/2332</topic><topic>82/51</topic><topic>82/80</topic><topic>96</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Bcl-2-Like Protein 11</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line, Tumor</topic><topic>Cisplatin - pharmacology</topic><topic>DNA Damage</topic><topic>Down-Regulation - drug effects</topic><topic>Epithelium - drug effects</topic><topic>Epithelium - metabolism</topic><topic>Forkhead Box Protein O3</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Immunology</topic><topic>Life Sciences</topic><topic>Membrane Proteins - metabolism</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Neuroblastoma - enzymology</topic><topic>Neuroblastoma - pathology</topic><topic>Original</topic><topic>original-article</topic><topic>Phosphorylation - drug effects</topic><topic>Phosphothreonine - metabolism</topic><topic>Protein Binding - drug effects</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tatsumi, Y</creatorcontrib><creatorcontrib>Takano, R</creatorcontrib><creatorcontrib>Islam, M S</creatorcontrib><creatorcontrib>Yokochi, T</creatorcontrib><creatorcontrib>Itami, M</creatorcontrib><creatorcontrib>Nakamura, Y</creatorcontrib><creatorcontrib>Nakagawara, A</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database (ProQuest)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tatsumi, Y</au><au>Takano, R</au><au>Islam, M S</au><au>Yokochi, T</au><au>Itami, M</au><au>Nakamura, Y</au><au>Nakagawara, A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2015-01-01</date><risdate>2015</risdate><volume>6</volume><issue>1</issue><spage>e1607</spage><epage>e1607</epage><pages>e1607-e1607</pages><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>B
NIP2 and Cdc42GAP homology (
B
CH)
m
otif-
c
ontaining molecule at the
c
arboxyl-terminal region
1
(
BMCC1
) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25611382</pmid><doi>10.1038/cddis.2014.568</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Springer Nature OA Free Journals; Nature Free; PubMed Central |
| subjects | 13/2 14/105 14/19 631/337 631/80/82/23 631/80/86 692/699/67/2332 82/51 82/80 96 Antibodies Apoptosis Apoptosis Regulatory Proteins - metabolism Bcl-2-Like Protein 11 Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell Line, Tumor Cisplatin - pharmacology DNA Damage Down-Regulation - drug effects Epithelium - drug effects Epithelium - metabolism Forkhead Box Protein O3 Forkhead Transcription Factors - metabolism Gene Knockdown Techniques Humans Immunology Life Sciences Membrane Proteins - metabolism Neoplasm Proteins - metabolism Neuroblastoma - enzymology Neuroblastoma - pathology Original original-article Phosphorylation - drug effects Phosphothreonine - metabolism Protein Binding - drug effects Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-bcl-2 - metabolism RNA, Small Interfering - metabolism Skin Neoplasms - metabolism Skin Neoplasms - pathology |
| title | BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis |
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