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KLF4

KLF4
KLF4
사용 가능한 구조
PDBOrtholog 검색: PDBe RCSB
식별자
에일리어스KLF4, EZF, GKLF, 크루펠 유사 인자 4(gut), 크루펠 유사 인자 4
외부 IDOMIM: 602253 MGI: 1342287 HomoloGene: 3123 GenCards: KLF4
맞춤법
종.인간마우스
엔트레즈

9314

16600

앙상블

ENSG00000136826

ENSMUSG00000003032

유니프로트

O43474

Q60793

RefSeq(mRNA)

NM_001314052
NM_004235

NM_010637

RefSeq(단백질)

NP_001300981
NP_004226

NP_034767

장소(UCSC)Chr 9: 107.48 ~107.49 MbChr 4: 55.53 ~55.53 Mb
PubMed 검색[3][4]
위키데이터
인간 보기/편집마우스 표시/편집

Kruppel 유사인자 4(KLF4, 내장 강화 Kruppel 유사인자 또는 GKLF)는 SP1 유사전사인자의 [5][6][7]비교적 큰 계열에 속하는 아연 손가락 전사인자 KLF 계열의 구성원이다.KLF4는 증식, 분화, 아포토시스 및 체세포 재프로그래밍 조절에 관여한다.또한 증거는 KLF4가 대장암을 [8]포함한 특정 암의 종양 억제제라는 것을 암시한다.그것은 다른 KLF, KLF2와 밀접한 관련이 있는 [6]3개의 C2H2-아연 핑거를 카르복실 말단에 가지고 있다.그것은 [9]핵에 위치하도록 신호를 보내는 두 개의 핵 위치 결정 시퀀스를 가지고 있다.배아줄기세포(ESC)에서 KLF4는 줄기 유사 능력을 나타내는 좋은 지표로 입증되었다.간엽 줄기세포(MSCs)에서도 동일한 사실이 제시된다.

인간에서 단백질은 513개의 아미노산으로 예측 분자량은 약 55kDa이며 KLF4 [10]유전자에 의해 암호화된다.KLF4 유전자는 침팬지, 붉은털원숭이, 개, 소, 쥐, 쥐, 닭, 제브라피시,[11] 개구리 등에 보존된다.KLF4는 [12]1996년에 처음 확인되었다.

상호 작용

KLF4는 p300-CBP 코액티베이터 [13][14][15]패밀리와 같은 특정 전사 코액티베이터와 N 말단을 통해 상호작용함으로써 전사를 활성화할 수 있습니다.KLF4에 의한 전사 억제는 표적 DNA 배열에 결합하기 위한 활성제와 경합하는 KLF4에 의해 이루어진다(9~12).[16][17][18][19]KLF4는 CREB 결합 [20]단백질과 상호작용하는 것으로 나타났다.

텔로머라아제(TERT) 효소 서브유닛의 프로모터에 존재하는 전사인자 Klf4가 β-카테닌과 복합체를 형성한 것으로 밝혀졌다.Klf4는 Tert 프로모터에서 β-catenin 축적을 위해 필요했지만 β-catenin이 [21]없는 경우 Tert 발현을 자극할 수 없었다.

기능.

KLF4는 다양한 기능을 가지고 있으며, 최근 몇 년 동안 그 기능 중 일부는 명백히 모순되지만, 주로 만능 줄기세포를 [22][23]유도하는 데 필수적인 4가지 핵심 요소 중 하나로 그것의 필수적인 역할을 발견한 이후 주목을 받고 있다.KLF4는 비분열 세포에서 고도로 발현되며, 그 과발현이 세포주기 [12][24][25][26][27]정지를 유도한다.KLF4는 DNA가 [24][26][27][28]손상되었을 때 세포 분열을 예방하는 데 특히 중요하다.KLF4는 또한 중심체와 염색체 수(유전자 안정성)[29][30][31]를 조절하고 세포 [32][33][34][35][36][37]생존을 촉진하는 데 중요하다.하지만, 일부 연구는 특정 조건 하에서 KLF4가 친세포 생존에서 [36][38][39][40]친세포 사망으로 역할을 바꿀 수 있다는 것을 밝혀냈다.

KLF4는 비분열 세포로 발현되며 장상피에서 말단적으로 분화되며, 여기서 KLF4는 장상피 항상성 조절(말단세포 분화 및 다양한 장상피 세포 [41][42][43][44]유형의 적절한 국재화)에 중요하다.KLF4는 [44]분화를 조절하는 유전자의 Wnt 시그널링 경로 유전자의 중요한 조절자이다.

KLF4 조직 그리고 상피 장벽 function[45][46]고 유전자 각막 항상성에 필요한 조절기 필요한 각막과 같은 여러 장기의으며 피부 투과성 장벽 기능의 발전에 필요한 피부를[47], 그리고 규정하고[48][49][50]은 뼈와 이빨 조직 표현된다.골격 개발mal가 남성을 대상으로 적절한 정자 형성에 중요하다 그것이 어디에 염증성 반응을 조정한다 마우스를 남성과 여성의 생식 tract[55]으며 염증성 자극에 대응하여 혈관 누출을 방지하기에 매우 중요한[56][57][58]혈관 내피 cells[59],[60]의 백혈구[51][52][53][54]상피 세포 cellul.아르곤 differentiation[61][62][63][64]과 확산,[64][65]월.e 콩팥은 체외에서[66] 배아줄기세포와 유도만능줄기세포(iPS)의 분화에 관여하며 그 조절장애는 일부 신장병리학과 [67][68][69]관련이 있다.

질병에서의 역할

질병에서 KLF4의 역할은 특정 조건에서는 하나의 역할을 할 수 있고 다른 조건에서는 완전히 반대 역할을 할 수 있는 상황에 따라 다르다는 증거가 여러 개 있다.

KLF4는 항종양 인자로 대장암,[70] [71]위암, 식도 편평상피암,[33][72] 장암,[73] 전립선암,[75] 방광암[74], 폐암 등 다양한 인간 암 유형에서 발현을 잃는다.

단, 구강 편평상피암[76] 및 원발성 유방관암 [77]등 일부 암 유형에서는 KLF4 발현 증가가 보고된 종양촉진제 역할을 할 수 있다.또한 피부에 KLF4가 과다 발현되어 과형성 및 [78]이형성을 유발하여 편평상피암으로 [79]발전하였다.식도 상피에서도 유사한 발견이 관찰되었으며, KLF4의 과발현이 결국 [80]생쥐에서 식도 편평상피암 발병으로 이어지는 염증을 증가시켰다.

상피-간막 전이(EMT)에서 KLF4의 역할도 논란이 되고 있다.췌장암,[81][82][83] 두경부암,[84] 자궁내막암,[85] 비인두암,[86] 전립선암[87],[88] 비소형 폐암의 경우와 같이 암세포의 줄기성을 촉진/유지하여 일부 시스템에서 EMT를 자극하는 것으로 나타났다.TGFβ 유도 EMT KLF4의 조건에서 전립선암[89] [90]및 췌장암과 같은 EMT를 촉진하는 것으로 나타난 것과 동일한 시스템에서 EMT를 억제하는 것으로 나타났다.또한 KLF4는 표피암,[91] 유방암,[36] 폐암,[92] 시스플라틴 내성 비인두암 [93]세포 및 간세포암 [citation needed]세포에서 EMT를 억제하는 것으로 나타났다.

KLF4는 대식세포 분극과[94] 아테롬성 [95][96][97]동맥경화증의 플라크 형성을 조절하여 혈관 염증을 조절하는 것으로 나타난 여러 혈관 질환에서 중요한 역할을 한다.항아테롬성 동맥경화 [96]인자인 아폴리포단백질 E를 상향 조절합니다.그것은 또한 혈관신생의 조절에 관여한다.중추신경계에서는 과잉발현이 혈관성형 [99]이상을 초래하는 반면, NOCH1 활동을 [98]조절하여 혈관신생을 억제할 수 있다.

KLF4는 대식세포,[18] 식도상피[80] 및 [100]생쥐의 화학유발 급성대장염과 같은 NF-δB 의존성 염증 경로를 매개하여 염증을 촉진할 수 있다.단, KLF4는 항염증 [59]자극에 대한 반응으로 내피세포 등의 염증 시그널링 활성화를 억제할 수도 있다.

KLF4는 DNA 손상에 대한 세포 반응에 필수적이다.γ-방사선 유도 DNA [26][27]손상 후 세포주기의 유사분열 진입을 방지하고, DNA 수복 메커니즘을 촉진하고(20) 조사세포가 프로그램된 세포사망(아포토시스)을 겪는 것을 방지한다(23,25,26).[32][34][35]한 연구에서, 생쥐의 장 상피에서 특이적으로 KLF4의 결실이 장 상피 재생 불능으로 이어지고 이러한 [35]생쥐의 사망률을 증가시키는 γ-방사선 유도 DNA 손상에 대한 생체 내 중요도가 밝혀졌다.

줄기세포의 중요성

Takahashi와 Yamanaka는 KLF4를 마우스 배아 및 성인 섬유아세포를 만능줄기세포([23]iPS)로 유도하는 데 필요한 4가지 요인 중 하나로 최초로 식별했다.이것은 성인 인간 [22]섬유아세포에도 해당되는 것으로 밝혀졌다.2006년부터 현재까지 줄기세포와 줄기세포 유도에 대한 임상 관련 연구에 대한 연구는 극적으로 증가했다(1900년부터 2005년까지의 약 60건에 비해 10,000건 이상의 연구 논문).줄기세포에서 KLF4의 역할에 대한 생체내 기능 연구는 드물다.최근 한 그룹이 장내 줄기세포의 특정 집단인 Bmi1+[37] 줄기세포에서 KLF4의 역할을 조사했다.이 장줄기세포 집단은 보통 분열이 느리고 방사선 손상에 내성이 있는 것으로 알려져 있으며 방사선 [101]손상에 따른 장상피 재생에 책임이 있다.연구결과 장내에서는 γ-방사선 유도 DNA 손상 후 KLF4가 Bmi1+(BMI1) 줄기세포 자체의 운명을 조절함으로써 상피 재생을 조절하고 결과적으로 Bmi1++ 장내줄기세포 유래 [37]계통의 발달을 조절하는 것으로 나타났다.

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레퍼런스

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