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中国结直肠癌诊疗规范（2015版）.pdf
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中华胃肠外科杂志2015年 10月第 18卷第 10期 Chin J Gastrointest Surg,October 2015,Vol.18,No.10 961 ?诊治指南? 按语 结直肠癌是我国最常见的恶性肿瘤之一,发病率和死亡呈逐年增高之势。 20世纪90年代始,国内结直肠 外科陆续成立,结直肠癌治疗模式日趋标准化、规范化。 然而,我国结直肠癌的治疗仍存在较大的地域不平衡性,各级 医院对其手术方式和放化疗方案等选择上存在一定的差异。 为提高我国结直肠癌的总体诊治水平,《中国结直肠癌诊 疗规范》 以下简称《规范》 应运而生。 第一版《规范》首次发布于2010年 见我刊第 13卷865-875 页 ,由国家卫计委 医政司牵头委托中华医学会组织专家进行制订, 是一部依据国际结直肠癌相关指南并适合我国具体情况的诊疗规 范。 5年来,在国家卫计委的大力支持下,中华医学会和中国抗癌协会等学术组织通过各种形式对《规范》进行了各地 巡讲,有效地规范了各级医院对结直肠癌的诊疗行为。 随着结直肠癌诊治领域新技术新药物的不断涌现,国际上的结直肠癌诊治指南也在不断更新。 因此,国家卫计委 医政管理局决定对第一版《规范》进行了修订。此次《规范》由我国结直肠癌领域的学科带头人顾晋教授和汪建平教授 为组长成立修订小组,邀请我国结直肠癌领域的专家在广泛征求意见的前提下,历经多次讨论,3次集体会议,几经易 稿,终于形成了《中国结直肠癌诊疗规范 2015版 》。 此次《规范》修订的意义主要在于体现国内外结直肠癌诊疗技术的进展和观念,同时,修订了旧版《规范》中存在 的一些瑕疵和疏漏,并考虑到我国地域广泛、经济水平和医学水平的差异,对内容作了精简和细化。 《规范》修订不追 求“高、大、上”,尽量做到既符合目前国际结直肠癌诊疗的潮流,又能够接
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免疫组化ki-67约百分之四十肿瘤细胞《+》，MLH1(+),MS....
免疫组化ki-67约百分之四十肿瘤细胞《...
病情描述（发病时间、主要症状、症状变化等）：免疫组化ki-67约百分之四十肿瘤细胞《+》，MLH1(+),MSH2(+),MSH6(+),PMS2(+),CDX2(+).HER2(+).请问这些是什么意思？曾经治疗情况和效果：刚做完乙状结肠癌手术，结果是t3n0m0，2期a想得到怎样的帮助：想知道需要化疗吗？这些英文是什么意思。是属于高危期吗？
我得了肝癌，肝脏一直都在疼，差不多疼了半个月了，开始还只是轻微的疼痛，可是后来就越来越疼，疼得饭都吃不下饭
我得了肝癌，肝脏一直都在疼，差不多疼了半个月了，开始还只是轻微的疼痛
我得了肝癌，肝脏一直都在疼，差不多疼了半个月了，开始还只是轻微的疼痛
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因不能面诊，医生的建议仅供参考
职称：医师
专长：中医科
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问题分析：你好，根据你的描述，恶性肿瘤手术后一般都需要进行常规化疗，以免癌细胞扩散，预防病情复发。意见建议：这些英文代表乙状结肠癌的病理类型和分期，建议你要定期复查结肠镜和病理检查，以免病情复发。
职称：主任医师
专长：擅长腹腔镜胃肠肿瘤微创手术，各类复杂肠癌的多学科联...
病例分析:请问详细的病理报告？发上来有助于判断。意见建议:两期肠癌部分需要化疗，需要看详细病理报告。
问免疫组化结果显示MLH1(3+)MSH2(3+)MSH6(3+)PMS2(2+)什么意思
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专长：食物中毒，药物中毒，重金属中毒
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指导意见：你的情况如果不出现不适症状可以不必治疗的，可以定期复查就可以了， 祝健康。。
问免疫组化：MSH2(+)MSH6(+)MLH1(+)PMS2(+)EGFR(+)是什么...
职称：医师
专长：胃、十二指肠溃疡,慢性胃炎,慢性溃疡性结肠炎
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问题分析：粗黑激素，混合性细胞瘤，表皮生长因子受体，都是阳性，基本可以确性是淋巴系统的癌症存在，建议最好做一下活检，更进一步明确诊断。患者现在还有其他情况吗？意见建议：淋巴系统癌的最佳治疗办法就是化疗，除了化疗没有其他的治疗方法。可以考虑用美罗华治疗，改善生活质量，化疗2个疗程后看患者情况怎么样。考虑下一步治疗方案。
问乳腺癌免疫组化结果Ki-67（+40%）是什么意思
职称：主治医师
专长：食管癌,胃癌,直肠癌,淋巴瘤,肺癌,结肠癌,畸胎瘤,类癌综合征,癌性疼痛,恶性肿瘤
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问题分析：Ki67是一种增殖细胞相关的核抗原，阳性说明癌细胞增殖活跃。结合你的乳腺癌病史，提示肿瘤细胞增殖是比较活跃的。意见建议：单纯Ki-67指数意义不大，也不能决定你的治疗方案，是要结合你的病理类型、免疫组化、术后分期来综合制定治疗方案的。
问免疫组化Ki-67(+50%)是什么意思？
职称：护士
专长：肿瘤，癌症，肾脏疾病
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病情分析： Ki67（+50%，是乳腺癌的免疫组化结果，容易复发和转移，需要高度警惕。
祝好！！！望采纳111！！
问免疫组化：MSH2(+)MSH6(+)MLH1(+)PMS2(+)EGFR(+)
职称：药师
专长：药品
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问题分析：因为切下的大病理未见淋巴转移，所以还是较为理想的，但是从多方面考虑，为延长生存周期，考虑还是做放化疗为好。意见建议：建议从各个综合考虑，做放疗也是较为吃苦的，会发生一定程度的放射性肠炎，而且如果做调强放疗，价格也是较高的，加之化疗药，要综合全面考虑。
问免疫组化结果：SY-、CgA-、Ki67+(30%)、MSH2+、MSH6+、...
职称：医生会员
专长：心脏病，妇科疾病
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病情分析： 治疗上主要为抗炎，首先得弄清病因，其次才谈得上治疗。希望你去正规的医院做相关的检查，弄清楚后在进行系统正规的治疗。
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采用有效的治疗方法，生存时间可以得到有效的保证，不能盲目放化疗
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按医嘱服药，并且在饮食上多注意，定期做身体检查...
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手术治疗是膀胱癌的主要治疗方法，一般也是首选的治疗方法。
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结肠癌是常见的消化道恶性肿瘤，占胃肠道肿瘤的第二位。好发部位为直肠及直肠与乙状结肠交界处，占60%，...
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评价成功！ATF2 (activating transcription factor 2)
Genetics and Cytogenetics in Oncology and Haematology
& && && && && && && &&&& && &
ATF2 (activating transcription factor 2)Written2007-07Pedro A Lazo, Ana Sevilla
Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain
Updated2012-10Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
LocusID (NCBI)
Location_base_pair
and ends at
bp from pter
( according to hg19-Feb_2009)&&
Fusion genes(updated 2016)DDIT3 (12q13.3) / ATF2 (2q31.1)
ATF2 (2q31.1) is sometimes confused with CREB1 (2q33.3), because an alias of ATF2 is CREB1, also because they are both CREB-related proteins, a family of transcription factors of the bZIP superfamily, whose members have the ability to heterodimerize with each other, and, finally, because CREB1, like
(but not ATF2 so far), is a fusion partner of
in various soft tissue tumors (, ) harboring a t(2;22)(q33;q12) or a
respectively (review in Huret, 2010).
& ATF2 gene structure based on data available in the Ensembl release 44. Upstream non-coding exons (green). Coding exons (pink), 3' untranslated sequence (red). The size of the exons in nucleotides is indicated below each exon. Exon number is indicated within the exon.
Description Gene size: 96 Kb.
Transcription Initiation codon located in exon 3. Normal message is 1518 nucleotides. Numerous splice variants (24 according to Ensembl). A small isoform of ATF2, ATF2-small (ATF2-sm), with a calculated mass of 15 kDa, has no histone acetyltransferase (HAT) activity, but, still, has the ability to bind CRE-containing DNA. ATF2-sm is only composed of the first two and last two exons of ATF2. Within the body of the uterus, ATF2 full length is expressed only in the lower segment, whereas there is a gradient of expression of the ATF2-sm protein with the highest level in the upper segment. A significant number of genes are differentially regulated by the ATF2-fl and ATF2-sm transcription factors (Bailey et al., 2002; Bailey and Europe-Finner, 2005).
Description ATF2 is one of 16 members of the ATF and CREB group of bZIP transcription factors, components of the activating protein 1 (AP-1). The canonical form of ATF2 is made of 505 amino acids, 54.537 kDa according to Swiss-Prot. ATF2 comprises from N-term to C-term a zinc finger (C2H2- DNA binding) (amino acids 25-49), a transactivation domain (aa 19-106, Nagadoi et al., 1999), two proline-rich domain, (involved in protein-protein interaction) (Pro202, 207, 210, 212, 214, 216, 222, 228, 231 and 243, 247, 251, 256, 259, 261, 263, 267, 269), two glutamine-rich domains (involved in transcriptional trans-activation) (Gln268, 271, 284, 285 and 306, 313, 316, 317), a basic motif (amino acids 351-374), and a leucine zipper domain (amino acids 380-408, and a nuclear export signal), making a basic leucine zipper required for dimerization, and involved in CRE-binding (Kara et al., 1990 and Swiss-Prot.). ATF2 contains two canonical nuclear localization signals (NLS) in its basic motif, and two nuclear export signal (NES) in its leucine zipper, one of which in N-term: (1)MKFKLHV(7) (Liu et al., 2006; Hsu and Hu, 2012).
Expression Ubiquitously expressed. High expression in brain and in regenerating liver (Takeda et al., 1991).
Localisation Cytoplasmic and nuclear protein. The nuclear transport signals (NLS and NES) contribute to the shuttling of ATF2 between the cytoplasm and the nucleus. ATF2 homodimers are localized in the cytoplasm, and prevent its nuclear import. Heterodimerization with
prevents nuclear export of ATF2. JUN-dependent nuclear localization of ATF2 occurs upon stimulating conditions (retinoic acid-induced differentiation and UV-induced cell death) (Liu et al., 2006). Phosphorylation of ATF2 on Thr52 by
(PKCE) promotes its nuclear retention and transcriptional activity (Lau et al., 2012). Stress- or damage-induced cytosolic localization of ATF2 could be associated with cell death (Lau and Ronai, 2012). When ATF2 translocates to the cytoplasm, it localizes at the mitochondrial outer membrane (Lau et al., 2012).
Function - ATF2 is a transcription factor. ATF2 forms a homodimer or a heterodimer with JUN (Hai and Curran, 1991), or other proteins (see below). - Typically, it binds to the cAMP-responsive element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many cellular promoters (Hai et al.,1989). However, depending on the heterodimeric partner, ATF2 binds to different response elements on target genes. ATF2/JUN and ATF2/CREB1 bind the above noted concensus sequence. ATF2 is mainly a transcription activator, but it also may be a transcription repressor (reviews in Bhoumik and Ronai, 2008; Lopez-Bergami et al., 2010; Lau and Ronai, 2012). Activation of ATF2 ATF2 is activated by stress kinases, including JNK (, , ) and p38 (, , , , ) and is implicated in transcriptional regulation of immediate early genes regulating stress and DNA damage responses (Gupta et al., 1995; van Dam et al., 1995) and cell cycle control under normal growth conditions.(up-regulation of the
(cyclin A) promoter at the G1/S boundary) (Nakamura et al., 1995). In response to stimuli, ATF2 is phosphorylated on threonine 69 and/or 71 by JNK or by p38. Phosphorylation on Thr69 and Thr71 of ATF2 and its dimerization are required to activate ATF2 transcription factor activity. Phosphorylation on Thr69 occurs through the --P38 pathway, and phosphorylation on Thr71 occurs through the RAS-MEK-ERK pathway (MAPK1,
(ERK1), MAPK11, MAPK12 and MAPK14) (Gupta et al., 1995; Ouwens et al., 2002). The intrinsic histone acetylase activity of ATF2 promotes its DNA binding ability (Abdel-Hafiz et al., 1992; Kawasaki et al., 2000). Interaction of ATF2 with
(CREB-binding protein, also called p300/CBP) is dependent upon phosphorylation at Ser121 induced by . ATF2 and CREBBP cooperate in the activation of transcription (Kawasaki et al., 1998; Yamasaki et al., 2009).
activates and stabilizes ATF2 through direct phosphorylation of Ser62 and Thr73 (Sevilla et al., 2004). Down regulation of ATF2 Among other down regulation mechanisms, ATF2 is down regulated, by
in response to ionizing radiation (Arora et al., 2011).
Transcriptionally active dimers of ATF2 protein are regulated by ubiquitylation and proteosomal degradation (Fuchs et al., 1999); phosphorylation of ATF2 on Thr69 and Thr71 promotes its ubiquitylation and degradation (Firestein and Feuerstein, 1998). A cytoplasmic alternatively spliced isoform of , ATF7-4, is a cytoplasmic negative regulator of both ATF2 and ATF7. It impairs ATF2 and ATF7 phosphorylation (ATF7-4 indeed sequesters the Thr53-phosphorylating kinase in the cytoplasm, preventing Thr53 phosphorylation of ATF7) and transcriptional activity (Diring et al., 2011). The activity of ATF2 is repressed by an intramolecular interaction between the N-terminal domain and the b-ZIP domain (Li and Green, 1996). The N-terminal nuclear export signal (NES) of ATF2 negatively regulates ATF2 transcriptional activity (Hsu and Hu, 2012). Dimerization of ATF2 The basic leucine zipper (basic motif + leucine zipper, "b-ZIP") of ATF2 enables homo- or hetero-dimerization.
The main dimerization partners of ATF2 are the following: ATF2, , CREB1, , JUN, , , , , , , POU2F1,
(Lau and Ronai, 2012). ATF2 homodimers have a low transcriptional activity.
(SIN1) binds to the b-ZIP region of ATF2, and also binds MAPK14, and is required for MAPK14-induced phosphorylation of ATF2 in response to osmotic stress, and activates the transcription of apoptosis-related genes (Makino et al., 2006). In response to stress, ATF2 binds to POU2F1 (OCT1), NFI, and BRCA1 to activate transcription of . The b-Zip region of ATF2 is critical for binding to BRCA1. ATF2 also binds and activates
(Maspin) (Maekawa et al., 2008). ATF2 also forms a heterodimer with JDP2, a repressor of AP-1. JDP2 inhibits the transactivation of JUN by ATF2 (Jin et al., 2002). ATF2 target genes Under genotoxic stress, a study showed that 269 genes were found to be bound by ATF2/JUN dimers. Immediate-early genes were a notable subset and included EGR family members,
family members, and JUN family members, but the largest group of genes belonged to the DNA repair machinery (Hayakawa et al., 2004, see below). Among the ATF2 target genes are : - Transcription factors, such as JUN, ,
(CHOP), FOS, JUNB, - DNA damage proteins (see below), - Cell cycle regulators (CCNA2, ), see below, - Regulators of apoptosis (see below and Hayakawa et al., 2004), - Growth factor receptors and cytokines such as
(Maekawa et al., 1999), IL8 (Agelopoulos and Thanos, 2006),
(Fas ligand),
(TNFalpha),
family (Herr et al., 2000; Faris et al., 1998),
- Proteins related with invasion such as
(Hamsa and Kuttan, 2012) and
(UPA): ATF2/JUN heterodimer binds to and activates PLAU (De Cesare et al., 1995), - Cell adhesion molecules, such as , , and
(Reimold et al., 2001), - Proteins engaged in the response to endoplasmic reticulum (ER) stress. ATF2/CREB dimers bind the CRE-like element TGACGTGA of
(Grp78) and activates it (Chen et al., 1997), - Genes encoding extracellular matrix components seem to constitute an important subset of ATF2/JUN-target genes (van Dam and Castellazzi, 2001). - , a negative regulator of the PI3K/AKT signaling pathway, is positively regulated by ATF2 (Qian et al., 2012). - ATF1 and ATF2 regulate
gene transcription. Histones, Chromatin UV treatment or ATF2 phosphorylation increases its histone acetyltransferase (HAT) activity as well as its transcriptional activities. Lys296, Gly297 and Gly299, are essential both for histone acetyltransferase activity and for transactivation (Kawasaki et al., 2000). Binding of ATF2 to the histone acetyltransferase
(TIP49b) suppresses ATF2 transcriptional activity. RUVBL2's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (Cho et al., 2001). ATF2 interacts with the acetyltransferase domains of CREBBP. ATF2 b-ZIP could serve as an acetyltransferase substrate for the acetyltransferase domains of CREBBP. ATF2 is acetylated on Lys357 and Lys374 by CREBBP, which contributes to its transcriptional activity (Karanam et al., 2007). ATF2 and ATF4 are essential for the transcriptional activation of DDIT3 (CHOP) upon amino acid starvation.
ATF2 is essential in the acetylation of histone H4 and H2B, and thereby may be involved in the modification of the chromatin structure. An ATF2-independent HAT activity is involved in the amino acid regulation of
transcription (Bruhat et al., 2007). The histone variant macroH2A recruitement into nucleosomes could confer an epigenetic mark for gene repression. The constitutive DNA binding of the ATF2/JUND heterodimer to the IL-8 enhancer recruits macroH2A-containing nucleosomes in B cells, thus inhibiting transcriptional activation (Agelopoulos and Thanos, 2006). Heat shock or osmotic stress induces phosphorylation of dATF2 (ATF2 in Drosophila), results in its release from heterochromatin, and heterochromatic disruption. dATF2 regulates heterochromatin formation. ATF2 may be involved in the epigenetic silencing of target genes in euchromatin. The stress-induced ATF2-dependent epigenetic change was maintained over generations, suggesting a mechanism by which the effects of stress can be inherited (Seong et al., 2011).
DNA damage response Phosphorylation on Ser490 and Ser498 by ATM is required for the activation of ATF2 in DNA damage response. Phosphorylation of ATF2 results in the localisation of ATF2 in ionizing radiation induced foci (in cells exposed to ionizing radiation (IR), several proteins phosphorylated by
translocate and colocalize to common intranuclear sites. The resulting IR-induced nuclear foci (IRIF) accumulate at the sites of DNA damage). ATF2 expression contributes to the selective recruitment of , , and
(NBS1) into IRIF. ATF2 is required for the IR-induced S phase checkpoint, and this function is independant of its transcriptional activity (Bhoumik et al., 2005).
(TIP60) is a histone acetyltransferase and chromatin-modifying protein involved in double strand breaks (DSB) repair, interacting with and acetylating ATM. ATF2 associates with KAT5 and RUVBL2. Under non-stressed conditions, ATF2 in cooperation with the ubiquitin ligase
promotes the degradation of KAT5 (Bhoumik et al., 2008a). Following genotoxic stress, 269 genes were found to be bound by ATF2/JUN dimers (see above), of which were 23 DNA repair or repair-associated genes (, , , , , RAD50, , , , , FOXN3 (CHES1), ,
(G22P1), , , , ATM, , , , and the DNA repair-associated ), derived from several recognized DNA repair mechanisms (Hayakawa et al., 2004). Cell Cycle
constrains cellular proliferation by activating the expression of the inhibitory growth factor
(TGF-beta 2) through ATF2 (Kim et al., 1992). CREB1 dimerizes with ATF2 to bind to the CCND1 (cyclin D1) promoter, to increase CCD1 expression (Beier et al., 1999). JUND dimerizes with ATF2 to repress
transcription, a protein necessary for the G1-to-S phase transition during the cell cycle, by binding to the proximal region of the CDK4-promoter, contributing to the inhibition of cell growth. The physical interactions of ATF2 with JUND implicates the b-ZIP domain of ATF2 (Xiao et al., 2010). Heterodimerization of JUND with ATF2 activates CCNA2 (cyclin A) promoter. CCNA2 is essential for the control at the G1/S and the G2/M transitions of the cell cycle. In contrast, ATF4 expression suppresses the promoter activation mediated by ATF2 (Shimizu et al., 1998). Apoptosis ATF2/CREB1 heterodimer binds to the CRE element of the
promoter (Ma et al., 2007). ATF2 induces
upregulation (Chen et al., 2010).
(ASK1) activates ATF2 and --BID signalling, resulting in the translocation of
and BAK, and subsequently mitochondrial dysregulation (Hassan et al., 2009). ATF2/JUN heterodimers bind and activate , a key executor of neuronal apoptosis (Song et al., 2011). Following death receptor stimulation, there is phosphorylation and binding of ATF2/JUN to death-inducing ligands promoters (FASLG, TNF, TNFSF10), which allows the spread of death signals (Herr et al., 2000). Neuronal apoptosis requires the concomitant activation of ATF2/JUN and downregulation of FOS (Yuan et al., 2009).
Many drugs are currently being tested for their ability to inhibit cell proliferation and induce apoptosis through various pathways, including ATF2 pathway. In the cytoplasm, ATF2 abrogates formation of complexes containing
and , deregulating mitochondrial outer-membrane permeability and initiating apoptosis. This function is negatively regulated phosphorylation of ATF2 by PRKCE, which dictates its nuclear localization (Lau et al., 2012). Metabolic control and Insulin signalling ATF2 has been implicated in the regulation of proteins involved in metabolic control, including the control of the expression of UCP1, a protein involved in thermogenic response in brown adipose tissue (Cao et al., 2004) and phosphoenolpyruvate carboxykinase (), a protein regulating gluconeogenesis (Cheong et al., 1998).
activates ATF2 by phosphorylation of Thr69 and Thr71 (Baan et al., 2006). Co-expression of ATF2, MAFA, PDX1, and TCF3 results in a synergistic activation of the insulin promoter in endocrine cells of pancreatic islets. ATF2, MAFA, PDX1, and TCF3 form a multi-protein complex to facilitate insulin gene transcription (Han et al., 2011).
ATF2 target genes in insulin signalling are ATF3, JUN, , DUSP1 (MKP1), and . Deregulation of these genes is linked to the pathogenesis of insulin resistance, beta-cell dysfunction and vascular complications found in type 2 diabetes. Therefore, aberrant ATF2 activation under conditions of insulin resistance may contribute to the development of type 2 diabetes (Baan et al., manuscript in preparation). Iron depletion
Iron depletion induced by chelators increases the phosphorylation of JNK and MAPK14, as well as the phosphorylation of their downstream targets
and ATF2 (Yu and Richardson, 2011).
MutationsNote v-Rel-mediated transformation suggests opposing roles for ATF2 in oncogenesis. The increase in ATF2 expression observed in v-Rel-transformed cells promotes oncogenesis. On the other hand, enhanced expression of ATF2 inhibits transformation by v-Rel. ATF2 can regulate signaling pathways in a cell type-specific and/or context-dependent manner. Differences were found in the stage at which ATF2 regulated the RAS/RAF/MAPK signaling pathway in fibroblast (where it blocked the activation of RAF, /, MAPK1/MAPK3) and in the lymphoid DT40 B-cell line (where overexpression of ATF2 increased
activity and phosphorylated . ATF2 exhibits both oncogenic and tumor suppressor properties (Liss et al., 2010).
Somatic V258I in
cell lines (Woo et al., 2002). K105T in
cell lines (Jones et al., 2008).
promoter activity, and further expression of , which suggests important role in neovascularization (Licht et al., 2006).
Entity Epithelial mesenchymal transition
Note Epithelial mesenchymal transition (EMT) is characterized by the loss of the epithelial cell properties and the development of mesenchymal properties of cells, with altered cytoskeletal organization and enhanced migratory and invasive potentials. EMT is seen in embryonic development, organogenesis, wound healing, and oncogenesis. TGF-beta induces EMT, and is up-regulated by ATF2 (Bakin et al., 2002; Venkov et al., 2011; Xu et al., 2012).
Entity Allergic asthma
Note In a mouse model of allergic asthma, Aspergillus fumigatus provokes the secretion TNF (TNFalpha) by A. fumigatus-activated macrophages. In response to TNF, ATF2/JUN, /RELA (p65/p65) and / complexes are recruited to the
enhancer in lung epithelial cells (Bickford et al., 2012).
Entity Autoimmune diseases
and ATF2 are activated during Theiler's virus (TMEV) infection (which may provoke an autoimmune demyelinating disease). SMAD3 and ATF2 activate IL-23 p19 promoter (Al-Salleeh and Petro, 2008). IL-23 consists of a p40 subunit
coupled to the p19 subunit , and has an essential role in the development of T cell-mediated autoimmune diseases (Inoue, 2010).
Entity Vascular homeostasis
Note CD39 is a transmembrane protein expressed on the surface of vascular and immune cells. CD39 inhibits platelet activation, maintains vascular fluidity, and provides protection from both cardiac and cerebral ischemia and reperfusion injuries. cAMP regulates CD39 expression through ATF2, which binds a CRE-like regulatory element lying 210 bp upstream of the CD39 transcriptional start point (Liao et al., 2010).
Entity Bone development
Note ATF2 promotes chondrocyte proliferation and cartilage development through CCND1 upregulation in chondrocytes (Beier et al., 1999); mice carrying a germline mutation in ATF2 have a defect in endochondral ossification (Reimold et al., 1996). ATF2 regulates the expression of RB1, which regulates the G1- to S-phase transition by sequestering the E2F family members, necessary for cell cycle progression. When E2Fs are released, the cell is committed to progress through the cell cycle, which is essential in regulating cell proliferation vs differentiation.of chondrocytes and endochondral bone growth (Vale-Cruz et al., 2008).
ATF2/CREB1 binds to CRE domain of
(RANKL) promoter and TNFSF11 expression stimulates osteoclastogenesis in mouse stromal/osteoblast cells (Bai et al., 2005). Binding of JUN CREB1, ATF1, and ATF2 complexes are required for COL24A1 transcription, a marker of late osteoblast differentiation (Matsuo et al., 2006). Luteolin, a flavonoid, inhibits TNFSF11-induced osteoclastogenesis through the inhibition of ATF2 phosphorylation (Lee et al., 2009).
Entity Brain
Note ATF2 is expressed with large variations in intensity (and often highly expressed), according to the brain region examined.
Altogether, ATF2 seems to play a fundamental role in neuronal viability and in neurological functions in the normal brain and is down-regulated in the hippocampus and the caudate nucleus in Alzheimer, Parkinson and Huntington diseases (Pearson et al., 2005).
Mice carrying a germline mutation in ATF2 had a reduced number of cerebellar Purkinje cells, atrophic vestibular sense organs, an ataxic gait, hyperactivity,and decreased hearing (Reimold et al., 1996). A missense mutation in ATF2 in dogs has shown to provoke an autosomal recessive disease with short stature and weakness at birth, ataxia and generalized seizures, dysplastic foci consisting of clusters of intermixed granule and Purkinje cells, and death before 7 weeks of age (Chen et al., 2008d). ATF2 plays critical roles for the expression of the
gene (tyrosine hydroxylase) and for neurite extension of catecholaminergic neurons (Kojima et al., 2008). Neuronal-specific ATF2 expression is required for embryonic survival, ATF2 has a strong pro-survival role in somatic motoneurons of the brainstem, and loss of functional ATF2 leads to hyperphosphorylated JNK and p38, and results in somatic and visceral motoneuron degeneration (Ackermann et al., 2011). On the other hand, activated ATF2 promotes apoptosis of various brain cells, of which are cerebellar granule neurons (Ramiro-Cort&s et al., 2011; Song et al., 2011). ATF2/JUN heterodimers bind and activate CASP3, a key executor of neuronal apoptosis, in cerebellar granule neurons (Song et al., 2011). ATF2/JUN heterodimers bind and activate
(DP5, death protein 5/harakiri), a proapoptotic gene, promoting the death of sympathetic neurons (Ma et al., 2007; Towers et al., 2009), but also ATF2/JUN binds to two conserved CRE sites in the
(MKP1) overexpression of DUSP1 inhibits JNK-mediated phosphorylation of JUN and protect sympathetic neurons from apoptosis (Kristiansen et al., 2010). ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses (Green et al., 2008), see Table 1.
Table 1. Induction of activating transcription factors in the nucleus accumbens and their regulation of emotional behavior. (from Green et al., 2008).
Entity Skin and skin cancers
Note Inhibition of ATF2 with increased JNK/JUN and JUND induces apoptosis of melanoma cells (Bhoumik et al., 2004).
downregulation is mediated by ATF2/JUNB-dependent suppression of
transcription (Shah et al., 2010); MITF is a transcription factor for tyrosinase () and plays a role in melanocyte development. ATF2 attenuates
susceptibility to apoptosis. ATF2 control of melanoma development is mediated through its negative regulation of SOX10 and consequently of MITF transcription. The ratio of nuclear ATF2 to MITF expression is associated with poor prognosis (Shah et al., 2010). Assignment to the low-risk group in stage II melanoma requires elevated levels of overall
(beta-catenin) and nuclear
(p21WAF1), decreased levels of , and distributions that favor nuclear concentration for
(p16INK4A) but cytoplasmic concentration for ATF2 (Gould Rothberg et al., 2009). Phosphorylated ATF2 (p-ATF2) is significantly overexpressed in cutaneous angiosarcoma (malignant tumor) and pyogenic granuloma (benign tumor) than in normal dermal vessels (Chen et al., 2008a); p-ATF2 is also overexpressed in cutaneous squamous cell carcinoma, Bowen's disease, and basal cell carcinomas, as compared to its expression in normal skin (Chen et al., 2008b).
p-ATF2 is also overexpressed in eccrine porocarcinoma and eccrine poroma (Chen et al., 2008c). ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2KI mice) are more sensitive to ionizing radiation IR, exhibit increased intestinal cell apoptosis, develop a higher number of low-grade skin tumors (papillomas, squamous cell carcinomas, spindle cell carcinomas) (Li et al., 2010). A decrease of nuclear ATF2 and high CTNNB1 (beta-catenin) expression is seen in squamous cell carcinoma and basal cell carcinoma, compared to normal skin, while the cytoplasmic ATF2 expression was not significantly different in cancer and normal skin (Bhoumik et al., 2008b). A nuclear localization of ATF2 would be associated with its oncogenic properties, and a cytosolic localization with its tumor suppressor properties (Lau and Ronai, 2012). High levels of ATF2/JUN dimers induce autocrine growth and primary tumor formation of fibrosarcomas in the chicken (van Dam and Castellazzi, 2001).
Entity Soft tissue sarcomas
Note In human and murine
cells with t(X;18)(p11.2;q11.2) and a hybrid -, BCL2 expression is increased, but other anti-apoptotic genes, including
are repressed via binding of ATF2 to the cAMP-responsive element (CRE) in the promoters of these genes (Jones et al., 2012).
Entity Leukemias
Note ATF2 was found to upregulate
in a human
cell line (Chen et al., 2009).
(NRF2) is a transcription activator of the bZIP family which binds to antioxidant response elements (ARE) in the promoter regions of target genes in response to oxidative stress. NFE2L2 positively regulates the expression the AP-1 family proteins ATF2, JUN and FOS. NFE2L2/ARE pathway plays an important role in the induction of differentiation of myeloid leukemia cells by 1alpha,25-dihydroxyvitamin D3 (1,25D), a strong differentiation agent (Bobilev et al., 2011). A crosstalk between NFE2L2 and ATF2 has also been noted in prostate cancer cells (Nair et al., 2010).
Note The loss of one copy of p53 in ATF2+/- mice led to mammary tumor development, which supports the notion that ATF2 and p53 independently activate SERPINB5 and GADD45 expression (Maekawa et al., 2008).
ATF2/JUN mediate increased BIM expression in response to MAPK14 (p38alpha) signaling in cells detached from the extracellular matrix, indicating a contributing role for ATF2 in regulating acinar lumen formation, crucial for the development of mammary gland development, a function that may be crucial to its ability to suppress breast cancer. (Wen et al., 2011). ATF2/JUN binds to a potential CRE element of , and induces its expression. FOXP3 acts as a transcriptional repressor of oncogenes such as
and , and is able to cause apoptosis of breast cancer cells. The use of this ATF2-FOXP3 pathway may be of potential interest in future therapeutic approach of breast cancer. (Liu et al., 2009). Aggressive basal-like breast cancer cells exhibit high expression of
(FRA1)/JUN dimers rather than ATF2/JUN dimers (Baan et al., 2010).
Note In PTEN-deficient endometrial cancers (which represent 1/3 to 3/4 of ), ATF2 is activated, while ATF2 shows a reduced expression in PTEN-positive endometrial cancers (Xiao et al., 2010).
Note Heparan-sulfate proteoglycans are required for maximal growth factor signaling in prostate cancer progression. HS2ST1 (heparan sulfate 2-O-sulfotransferase, 2OST) is essential for maximal proliferation and invasion. HS2ST1 is upregulated by ATF2 (Ferguson and Datta, 2011).
Note Patients with lung cancer showing high
expression in cancer cells had a poor prognosis. ANGPTL2 increases tumor angiogenesis, enhances tumor cell motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. NFATc ( to
and ) function in tumor cell development and metastasis. It has been found that NFATc form a complex with ATF2/JUN heterodimers that bind to the CRE site of ANGPTL2 and enhances ANGPTL2 expression (Endo et al., 2012).
Entity Other cancers
Note Increased expression of ATF2 and ATF1 in nasopharyngeal carcinoma cells was associated with clinical stages (Su et al., 2011).
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CitationThis paper should be referenced as such :
ATF2 (activating transcription factor 2)
Atlas Genet Cytogenet Oncol Haematol. ):167-177.
Free journal version :
On line version :
History of this paper:
Lazo, PA ; Sevilla, A. ATF2 (activating transcription factor 2). Atlas Genet Cytogenet Oncol Haematol. ):33-34.
&&activating transcription factor 2
AliasesCRE-BP1;&CREB-2;&CREB2;&HB16;&TREB7
[Gene_View]&& [Contig_View]&& [Vega]
[Gene_View]&& [Contig_View]&& [Vega]
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(SM00338)&& (SM00355)&&
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