劉可美， 顏紅兵

(國(guó)家心血管病中心， 中國(guó)醫(yī)學(xué)科學(xué)院阜外醫(yī)院， 北京協(xié)和醫(yī)學(xué)院， 北京 100037)

·綜 述·

Wip1相關(guān)研究進(jìn)展*

劉可美， 顏紅兵△

(國(guó)家心血管病中心， 中國(guó)醫(yī)學(xué)科學(xué)院阜外醫(yī)院， 北京協(xié)和醫(yī)學(xué)院， 北京 100037)

Wip1； 腫瘤； 衰老； 免疫； 炎癥； 代謝

Fiscella等[1]首次通過γ射線或UV射線誘導(dǎo)發(fā)現(xiàn)了野生型p53誘導(dǎo)的磷酸酶1(wild-type p53-induced phosphatase 1，Wip1),并且證實(shí)Wip1的表達(dá)依賴于p53。編碼Wip1蛋白的基因稱為PPM1D，定位于人染色體17q23和小鼠第11號(hào)染色體上，PPM1D編碼的mRNA在很多器官組織包括睪丸和心臟中表達(dá)[2]。人Wip1蛋白包含605個(gè)氨基酸，分子量大約為66 kD，屬于蛋白磷酸酶2C(type 2C protein phosphatase，PP2C)家族[3]。Wip1蛋白序列分為2個(gè)主要的結(jié)構(gòu)域，N端第1～375個(gè)氨基酸是高保守的磷酸酶結(jié)構(gòu)域，第376～605個(gè)氨基酸是低保守的非催化區(qū)，可能與Wip1的核定位有關(guān)[4]。很多應(yīng)激如電離輻射、紫外線照射、茴香霉素、過氧化氫、甲烷磺酸鹽和炎癥因子等可以誘導(dǎo)Wip1表達(dá)。誘導(dǎo)活化后，Wip1可與應(yīng)激通路中一些重要的信號(hào)蛋白如p38絲裂原活化蛋白激酶(p38 mitogen-activated protein kinase，p38 MAPK)結(jié)合并使其去磷酸化，從而使其失活或活化。通過去磷酸化作用，Wip1在機(jī)體內(nèi)發(fā)揮著調(diào)節(jié)細(xì)胞周期、抑制凋亡、抑制DNA修復(fù)和抑制炎癥等功能[5]。

1 Wip1的生理調(diào)節(jié)作用

Wip1在個(gè)體發(fā)育過程中起著重要的生理調(diào)節(jié)作用。Wip1基因敲除(Wip1 knockout, Wip1-KO)小鼠有一系列發(fā)育異常，包括雄鼠發(fā)育不全、生殖器官萎縮、生殖能力下降和壽命縮短[3]。敲除Wip1基因的雄鼠輸精管和附睪發(fā)育異常導(dǎo)致生殖功能缺陷，而壽命縮短可能是激素水平失衡或類固醇受體活化受限引起的。Wip1可以通過增強(qiáng)類固醇受體共激活劑1的固有活性刺激類固醇受體，從而正向調(diào)節(jié)雌激素、黃體酮和雄激素受體活性[6]。此外，Wip1在成年神經(jīng)細(xì)胞生成中也有著重要的調(diào)節(jié)作用。Wip1缺失的神經(jīng)干細(xì)胞的細(xì)胞周期延長(zhǎng)，細(xì)胞聚集在G2期，細(xì)胞內(nèi)p53磷酸化上調(diào)，導(dǎo)致依賴p53的細(xì)胞周期抑制因子如p21和Reprimo表達(dá)增加。Zhu等[7]應(yīng)用Wip1和p53雙基因敲除小鼠證實(shí)p53在Wip1調(diào)節(jié)神經(jīng)干細(xì)胞中的作用。在Wip1-KO小鼠中敲除p53可以完全逆轉(zhuǎn)Wip1缺失引起的細(xì)胞周期受損，并使神經(jīng)干細(xì)胞和成神經(jīng)細(xì)胞數(shù)量增多，提示W(wǎng)ip1可以通過p53調(diào)節(jié)神經(jīng)干細(xì)胞的細(xì)胞周期[7]。其它蛋白包括p38 MAPK和毛細(xì)血管擴(kuò)張共濟(jì)失調(diào)突變蛋白(ataxia-telangiectasia mutated protein, ATM)等DNA損傷修復(fù)分子也與Wip1調(diào)節(jié)成年神經(jīng)細(xì)胞生成有關(guān)[8]。

2 Wip1與腫瘤

2002年，Li等[9]和Bulavin等[10]分別報(bào)道了Wip1在乳腺癌發(fā)生發(fā)展中起著重要作用。乳腺癌細(xì)胞系中，位于17q23位點(diǎn)的PPM1D發(fā)生擴(kuò)增，其可以通過調(diào)節(jié)細(xì)胞凋亡和細(xì)胞轉(zhuǎn)化促進(jìn)致癌表型[9]。Bulavin 等[10]在326例原發(fā)性乳腺癌患者中發(fā)現(xiàn)37例患者存在PPM1D擴(kuò)增，在PPM1D擴(kuò)增的8例患者中有7例患者PPM1D 的mRNA過表達(dá)。此后，Wip1在其它腫瘤中的作用陸續(xù)被報(bào)道，包括成神經(jīng)管母細(xì)胞瘤[11]、胰腺癌[12]、慢性淋巴細(xì)胞白血病[13]、肺癌[14]和肝癌[15]等。

Wip1促進(jìn)腫瘤發(fā)生發(fā)展的主要機(jī)制是直接或間接抑制包括p38 MAPK、ATM、細(xì)胞周期檢測(cè)點(diǎn)激酶2 (checkpoint kinase 2，CHK2)、鼠雙微小體2(murine double minute 2, MDM2)和p53等抑癌通路。首個(gè)被發(fā)現(xiàn)的Wip1作用靶點(diǎn)是p38 MAPK，Wip1可使p38 MAPK第180位點(diǎn)蘇氨酸去磷酸化，減少p38 MAPK的核定位并進(jìn)一步降低p53的激酶活性[16]。雙鏈DNA損傷可激活A(yù)TM激酶，活化的ATM激酶在細(xì)胞周期、DNA修復(fù)、凋亡和腫瘤形成方面起著重要的調(diào)節(jié)作用。通過促進(jìn)ATM第1 981位和第367位絲氨酸去磷酸化，Wip1可以抑制依賴ATM的DNA損傷修復(fù)通路，進(jìn)而促進(jìn)腫瘤的發(fā)生發(fā)展[17-18]。與ATM類似，CHK2活化在DNA損傷修復(fù)中也起著重要調(diào)節(jié)作用。體外研究顯示W(wǎng)ip1可以使CHK2第68位蘇氨酸去磷酸化，從而影響CHK2的活性[19]。DNA損傷引起的ATM活化可誘導(dǎo)MDM2第395位點(diǎn)絲氨酸磷酸化，減少M(fèi)DM2與p53的相互作用，從而使p53趨于穩(wěn)定。在Wip1作用下，MDM2第395位點(diǎn)絲氨酸去磷酸化，進(jìn)而影響p53穩(wěn)定性和抑癌作用[20]。腫瘤抑制因子p53是DNA損傷修復(fù)的中心節(jié)點(diǎn)，可通過調(diào)節(jié)細(xì)胞周期檢查點(diǎn)、DNA修復(fù)和凋亡而抑制腫瘤的發(fā)生發(fā)展。除了上述間接作用外，Wip1還可直接作用于p53第15位絲氨酸，使其去磷酸化而影響p53活性[21]。

鑒于Wip1在腫瘤中的重要作用，是否可以通過Wip1抑制劑治療腫瘤便成為進(jìn)一步研究方向。2014年，Gilmartin等[22]研究發(fā)現(xiàn)Wip1的小分子抑制劑GSK2830371可以通過一個(gè)扁平結(jié)構(gòu)域結(jié)合至Wip1的催化部位，此催化部位可將Wip1與其它PP2C家族成員區(qū)分，因而保證藥物對(duì)Wip1的高選擇性。應(yīng)用GSK2830371可抑制造血腫瘤細(xì)胞系和Wip1擴(kuò)增的乳腺癌細(xì)胞系生長(zhǎng)，小鼠口服GSK2830371對(duì)抑制淋巴瘤也取得較好療效。應(yīng)用GSK2830371治療可以改善DNA損傷修復(fù)通路，通過p21信號(hào)通路使細(xì)胞聚集在細(xì)胞周期的G1和G2期。聯(lián)合應(yīng)用GSK2830371和阿霉素或MDM2拮抗劑nutlin-3可通過增加p53第15位點(diǎn)絲氨酸磷酸化和第382位點(diǎn)賴氨酸乙?；T導(dǎo)p53通路激活，增加p53目的基因產(chǎn)物表達(dá)和活化凋亡相關(guān)的蛋白酶caspase-9，從而促進(jìn)細(xì)胞凋亡[23-24]。

3 Wip1與衰老

衰老可以導(dǎo)致很多器官功能下降，遺傳、環(huán)境和行為學(xué)因素都可能影響衰老，但具體的分子學(xué)機(jī)制尚不清楚。有研究顯示細(xì)胞周期素依賴蛋白激酶抑制蛋白(inhibitor of CDK4，Ink4α)與替代閱讀框(alternative reading frame，Arf)是衰老的標(biāo)志和效應(yīng)分子。隨著年紀(jì)增長(zhǎng)，Ink4α與Arf表達(dá)增加，導(dǎo)致具有自我更新功能的成體干細(xì)胞的增殖減少[25]。胰腺β細(xì)胞中Wip1的表達(dá)隨年齡增長(zhǎng)而逐漸減少[26]。老年胰腺的β細(xì)胞在應(yīng)激情況下不具有增殖能力，對(duì)胰島素分泌的適應(yīng)性下降而導(dǎo)致2型糖尿病。在Wip1-KO小鼠模型，胰島中Ink4α與Arf表達(dá)增加而β細(xì)胞增殖減少。通過減少p38 MAPK磷酸化，Wip1過表達(dá)可降低Ink4α與Arf表達(dá)，進(jìn)而改善衰老引起的胰島增殖功能下降[26]。因此，Wip1可能通過p38 MAPK通路調(diào)節(jié)胰腺衰老過程。Lee等[27]發(fā)現(xiàn)人間充質(zhì)干細(xì)胞隨年齡增長(zhǎng)發(fā)生的增殖衰減與p38 MAPK活性增加和Ink4α表達(dá)上調(diào)有關(guān)。過表達(dá)Wip1可以抑制p38 MAPK活性并減少Ink4α增加，進(jìn)而恢復(fù)間充質(zhì)干細(xì)胞的增殖能力。Wip1在早期成骨細(xì)胞中高表達(dá)，但表達(dá)量隨著細(xì)胞擴(kuò)增而下降，從而引起成骨細(xì)胞異常表型和纖維軟骨替代組織形成減少。穩(wěn)定表達(dá)Wip1的成骨細(xì)胞對(duì)衰老和分化不敏感，對(duì)氧化應(yīng)激的抵抗力更強(qiáng)，這種抵抗力與p38 MAPK活性相關(guān)。表達(dá)Wip1的成骨細(xì)胞還可以在較長(zhǎng)時(shí)間內(nèi)保持固有的成骨特性，從而改善移植后的軟骨再生[28]。

Wip1也能通過其它信號(hào)通路影響衰老過程。缺失Wip1的神經(jīng)干細(xì)胞的表型隨年齡增加逐漸加重，某些特殊位點(diǎn)的p53磷酸化增加。各種刺激引起的p53活化可導(dǎo)致大腦中成體干細(xì)胞減少，而敲除p53可以改善Wip1-KO小鼠的神經(jīng)干細(xì)胞表型[7]。在室管膜下層中僅有神經(jīng)干細(xì)胞可以表達(dá)WNT信號(hào)通路抑制劑DKK3，DKK3可以抑制成神經(jīng)細(xì)胞形成，敲除DKK3或藥物激活WNT信號(hào)通路可以改善年老小鼠的神經(jīng)元形成和嗅覺功能[29]。因此，Wip1可以通過WNT信號(hào)通路調(diào)節(jié)衰老過程中的神經(jīng)元分化。Chen等[30]發(fā)現(xiàn)Wip1可以通過傳統(tǒng)的p53通路調(diào)節(jié)造血干細(xì)胞分化以及mTORC1信號(hào)通路調(diào)節(jié)造血干細(xì)胞擴(kuò)增。缺失Wip1的小鼠干細(xì)胞表現(xiàn)為多種衰老表型，包括細(xì)胞池增大和再生能力受損。敲除p53可以在不影響細(xì)胞衰老或凋亡的情況下改善Wip1缺失引起的造血干細(xì)胞再生缺陷[30]。與野生型小鼠胚胎成纖維細(xì)胞相比，Wip1-KO小鼠胚胎成纖維細(xì)胞在傳統(tǒng)培養(yǎng)條件下表現(xiàn)為早衰，細(xì)胞中組蛋白2A變異體(histone family 2A variant，H2AX)磷酸化水平增加，提示W(wǎng)ip1可以通過調(diào)節(jié)DNA損傷修復(fù)通路防止DNA復(fù)制過程中內(nèi)源性雙鏈斷裂引起的細(xì)胞早衰[31]。

4 Wip1與免疫及炎癥

Wip1-KO小鼠存在免疫缺陷。敲除Wip1基因的小鼠出現(xiàn)皮膚潰瘍，淋巴器官紊亂或增生，正常組織中炎癥增加，體內(nèi)B細(xì)胞和T細(xì)胞失衡，對(duì)抗原和有絲分裂刺激反應(yīng)低下[32]。Schito等[33]發(fā)現(xiàn)Wip1在雙陰性T細(xì)胞轉(zhuǎn)變?yōu)殡p陽(yáng)性T細(xì)胞的過程中起著重要作用。相對(duì)于野生型小鼠，Wip1-KO小鼠的胸腺較小，胸腺中T細(xì)胞數(shù)量較少并且發(fā)育異常。在Wip1-KO小鼠中敲除p53可以使異常的胸腺表型恢復(fù)正常。中性粒細(xì)胞在宿主防御和組織修復(fù)中有重要作用。Liu等[34]報(bào)道Wip1在骨髓祖細(xì)胞向成熟中性粒細(xì)胞分化過程中表達(dá)增加，Wip1缺失可損害骨髓祖細(xì)胞向中性粒細(xì)胞的分化過程，Wip1調(diào)節(jié)中性粒細(xì)胞的發(fā)育、成熟和穩(wěn)態(tài)主要是通過p38 MAPK-信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄激活因子1(signal transducer and activator of transcription 1, STAT1)-CCAAT/增強(qiáng)子結(jié)合蛋白(CCAAT/enhancer-binding protein, C/EBP)信號(hào)通路。另外，Wip1對(duì)B細(xì)胞的發(fā)育成熟也起著調(diào)節(jié)作用。Wip1-KO小鼠的骨髓、外周血液和脾臟中B細(xì)胞數(shù)量明顯減少，早期B細(xì)胞前體表現(xiàn)出細(xì)胞內(nèi)在缺陷。Wip1缺失可使B細(xì)胞中p53持續(xù)活化，引起B(yǎng)細(xì)胞前體池凋亡增加，敲除p53可完全挽救Wip1缺失引起的B細(xì)胞發(fā)育受損。因此，Wip1缺失通過活化p53通路使早期B細(xì)胞前體凋亡增加進(jìn)而損害B細(xì)胞發(fā)育[35]。

人和小鼠中性粒細(xì)胞被激活后Wip1表達(dá)減少，膿毒癥患者體內(nèi)中性粒細(xì)胞中Wip1表達(dá)水平與炎癥因子合成呈負(fù)相關(guān)，提示W(wǎng)ip1可能影響炎癥反應(yīng)。進(jìn)一步研究發(fā)現(xiàn)，Wip1-KO小鼠對(duì)金黃色葡萄球菌的抗菌活性更強(qiáng)，對(duì)脂多糖引起的急性肺損傷更敏感，中性粒細(xì)胞浸潤(rùn)和炎癥反應(yīng)更嚴(yán)重。Wip1缺失可通過p38 MAPK-STAT1和NF-κB信號(hào)通路提高中性粒細(xì)胞的炎癥活性和遷移[36]。與野生型小鼠相比，Wip1-KO小鼠對(duì)葡聚糖硫酸鈉(dextran sulfate sodium，DSS)誘導(dǎo)的大腸炎更為易感，患病后生存率更低，疾病活動(dòng)指數(shù)更高，大腸病理表現(xiàn)更嚴(yán)重。給予DSS的野生型小鼠和Wip1-KO小鼠中性粒細(xì)胞中白細(xì)胞介素17(interleukin-17，IL-17)高表達(dá)，在Wip1-KO小鼠中敲除IL-17可以明顯減輕Wip1-KO小鼠的病理表型。因此，Wip1可以通過影響免疫細(xì)胞和IL-17表達(dá)調(diào)節(jié)宿主對(duì)大腸炎的敏感性[37]。在脂多糖腹側(cè)注射誘導(dǎo)的成年大鼠神經(jīng)炎模型中，Wip1在產(chǎn)生炎癥的大腦皮層活性星形膠質(zhì)細(xì)胞中表達(dá)增加。體外實(shí)驗(yàn)也顯示，被脂多糖活化的星形膠質(zhì)細(xì)胞中Wip1表達(dá)上調(diào)，通過siRNA阻斷Wip1可以抑制星形膠質(zhì)細(xì)胞中TNF-α的合成[38]。因此，Wip1在中樞神經(jīng)系統(tǒng)免疫反應(yīng)中也起著重要作用。

5 Wip1與代謝性疾病

Le Guezennec等[39]報(bào)道了Wip1可通過調(diào)節(jié)自噬和膽固醇流出影響肥胖和動(dòng)脈粥樣硬化。敲除Wip1可促進(jìn)脂質(zhì)轉(zhuǎn)化為載脂蛋白A1(apolipoprotein A1，apoA1)和高密度脂蛋白，抑制巨噬細(xì)胞轉(zhuǎn)變成泡沫細(xì)胞，這個(gè)過程與ATM、自噬和溶酶體酸酯酶(lysosomal acid lipase，LAL)等信號(hào)通路相關(guān)?；贚AL自噬依賴的脂質(zhì)流出可能是Wip1逆轉(zhuǎn)早期動(dòng)脈粥樣硬化斑塊的機(jī)制。在動(dòng)脈粥樣硬化形成過程的后期，Wip1可通過哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)信號(hào)通路和自噬影響斑塊進(jìn)展[39]。Wip1還能調(diào)節(jié)血糖代謝過程。在小鼠胚胎成纖維細(xì)胞中敲除Wip1可降低胰島素調(diào)節(jié)的AKT活性[40]。給予低脂飲食或高脂飲食的Wip1-KO小鼠或Wip1-KO小鼠胚胎成纖維細(xì)胞中促炎細(xì)胞因子表達(dá)增加，Wip1-KO小鼠出現(xiàn)糖耐量異常和胰島素抵抗，炎癥反應(yīng)增加可能是Wip1-KO小鼠在低脂和高脂飲食時(shí)產(chǎn)生胰島素抵抗的原因[40]。

綜上所述，隨著研究越來越深入和全面，作為致癌基因被大家熟知的Wip1的其它作用逐漸被發(fā)現(xiàn)。通過影響不同的信號(hào)通路，Wip1不僅僅作用于腫瘤的發(fā)生發(fā)展，在生理發(fā)育、衰老、免疫、炎癥和代謝方面也起著重要作用。雖然Wip1抑制劑在細(xì)胞水平和動(dòng)物模型中均有較好效果，但目前仍沒有關(guān)于Wip1抑制劑在人類腫瘤中的作用和臨床療效的報(bào)道，其是否能應(yīng)用于臨床并取得較好療效仍需要大量研究。Wip1可通過調(diào)節(jié)脂質(zhì)代謝影響動(dòng)脈粥樣硬化形成，而脂質(zhì)代謝及動(dòng)脈粥樣硬化與心血管疾病如心肌梗死關(guān)系密切，Wip1是否在心肌梗死及預(yù)后中有一定作用也需進(jìn)一步探討。若這些問題得到解答，一定可以提供更多的關(guān)于Wip1的信息并服務(wù)于臨床實(shí)踐，以期改善臨床患者的預(yù)后。

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(責(zé)任編輯： 林白霜， 羅 森)

Progress in the role of Wip1

LIU Ke-mei, YAN Hong-bing

(NationalCenterforCardiovascularDiseases,FuwaiHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing100037,China.E-mail:hbyanfuwai@aliyun.com)

Wildtype p53-induced phosphatase 1 (Wip1) is a serine/threonine protein phosphatase of 605 amino acids, which is expressed at high levels in many organs and tissues. As Wip1 is overexpressed in human tumors, analysis of Wip1 has focused primarily on its role in tumorigenesis. In recent years, it has also been shown that Wip1 plays an important role in several physiological processes including adult neurogenesis, senescence, immunodeficiency and metabolic diseases. This review addresses how Wip1 participates in physiological and pathological conditions at cellular and molecular levels.

Wip1; Tumor; Senescence; Immune; Inflammation; Metabolism

1000- 4718(2017)03- 0562- 05

2016- 09- 18

2016- 10- 14

國(guó)家自然科學(xué)基金資助項(xiàng)目(No. 81270288； No. 81541095)

△通訊作者 Tel: 010-88322281； E-mail: hbyanfuwai@aliyun.com

R363

A

10.3969/j.issn.1000- 4718.2017.03.031