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Blood：NR4A1和NR4A3通过调控C/EBPα和炎性信号抑制HSC增殖

2018-02-23 MedSci MedSci原创

NR4A1NR4A3HSC增殖炎性应答
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NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的、相互重复的作用，此外还具有对血液恶性肿瘤的抑制作用。既往研究认为NR4A1和NR4A3在AML发展中，肿瘤抑制作用相互重叠。但其在造血干细胞（HSC）稳态中的作用尚未完全清楚。现研究人员利用条件下敲除Nr4a1/Nr4a3的小鼠模型（CDKO）发现，共敲除NR4A1/3可促进HSC稳态发生急剧变化，包括丧失HSC静止、过氧应激累积和DNA损伤

NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的、相互重复的作用，此外还具有对血液恶性肿瘤的抑制作用。既往研究认为NR4A1和NR4A3在AML发展中，肿瘤抑制作用相互重叠。但其在造血干细胞（HSC）稳态中的作用尚未完全清楚。

现研究人员利用条件下敲除Nr4a1/Nr4a3的小鼠模型（CDKO）发现，共敲除NR4A1/3可促进HSC稳态发生急剧变化，包括丧失HSC静止、过氧应激累积和DNA损伤，但可维持干细胞自我更新和分化的能力。

CDKO HSCs的分子图谱分析发现，调控细胞周期和炎症的基因程序广泛上调、干扰素和NF-κB信号通路在无刺激的情况下异常激活。机制上，研究人员证明NR4A1/3可通过直接结合至造血特异性Cebpa增强子从而激活C/EBPα所驱动的抗增殖网络以及激活Cebpa转录来抑制HSC增殖。此外，NR4A1/3可结合至NF-κB调节的炎性细胞因子的调控区，进而拮抗NF-κB信号的激活作用。

总而言之，本研究结果揭示了NR4A1/3通过直接激活C/EBPα和抑制NF-κB驱动的增殖性炎性应答激活协同调控HSC静止的新机制。

原始出处：

Pablo R. Freire and Orla M. Conneely.NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling.Blood  2018  ：blood-2017-07-795757；  doi： https：//doi.org/10.1182/blood-2017-07-795757

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  1. [GetPortalCommentsPageByObjectIdResponse(id=1658598, encodeId=a996165859813, content=<a href='/topic/show?id=4d06914052' target=_blank style='color:#2F92EE;'>#HSC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=9140, encryptionId=4d06914052, topicName=HSC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f4bd24890262, createdName=sjq035, createdTime=Tue Jun 19 08:30:00 CST 2018, time=2018-06-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292255, encodeId=ca8b29225582, content=签到学习了--, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eeef1960262, createdName=杨柳青青, createdTime=Fri Mar 02 09:52:06 CST 2018, time=2018-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290848, encodeId=568c290848d4, content=学习一下, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Sun Feb 25 18:06:56 CST 2018, time=2018-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290276, encodeId=41382902e6d4, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:49 CST 2018, time=2018-02-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290275, encodeId=568e2902e5eb, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:26 CST 2018, time=2018-02-23, status=1, ipAttribution=)]
    2018-06-19 sjq035

    #HSC#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1658598, encodeId=a996165859813, content=<a href='/topic/show?id=4d06914052' target=_blank style='color:#2F92EE;'>#HSC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=9140, encryptionId=4d06914052, topicName=HSC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f4bd24890262, createdName=sjq035, createdTime=Tue Jun 19 08:30:00 CST 2018, time=2018-06-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292255, encodeId=ca8b29225582, content=签到学习了--, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eeef1960262, createdName=杨柳青青, createdTime=Fri Mar 02 09:52:06 CST 2018, time=2018-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290848, encodeId=568c290848d4, content=学习一下, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Sun Feb 25 18:06:56 CST 2018, time=2018-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290276, encodeId=41382902e6d4, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:49 CST 2018, time=2018-02-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290275, encodeId=568e2902e5eb, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:26 CST 2018, time=2018-02-23, status=1, ipAttribution=)]
    2018-03-02 杨柳青青

    签到学习了--

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=1658598, encodeId=a996165859813, content=<a href='/topic/show?id=4d06914052' target=_blank style='color:#2F92EE;'>#HSC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=9140, encryptionId=4d06914052, topicName=HSC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f4bd24890262, createdName=sjq035, createdTime=Tue Jun 19 08:30:00 CST 2018, time=2018-06-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292255, encodeId=ca8b29225582, content=签到学习了--, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eeef1960262, createdName=杨柳青青, createdTime=Fri Mar 02 09:52:06 CST 2018, time=2018-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290848, encodeId=568c290848d4, content=学习一下, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Sun Feb 25 18:06:56 CST 2018, time=2018-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290276, encodeId=41382902e6d4, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:49 CST 2018, time=2018-02-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290275, encodeId=568e2902e5eb, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:26 CST 2018, time=2018-02-23, status=1, ipAttribution=)]
    2018-02-25 wxl882001

    学习一下

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1658598, encodeId=a996165859813, content=<a href='/topic/show?id=4d06914052' target=_blank style='color:#2F92EE;'>#HSC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=9140, encryptionId=4d06914052, topicName=HSC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f4bd24890262, createdName=sjq035, createdTime=Tue Jun 19 08:30:00 CST 2018, time=2018-06-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292255, encodeId=ca8b29225582, content=签到学习了--, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eeef1960262, createdName=杨柳青青, createdTime=Fri Mar 02 09:52:06 CST 2018, time=2018-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290848, encodeId=568c290848d4, content=学习一下, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Sun Feb 25 18:06:56 CST 2018, time=2018-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290276, encodeId=41382902e6d4, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:49 CST 2018, time=2018-02-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=290275, encodeId=568e2902e5eb, content=NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚., beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7cJ6ejWUr2nIia8qOvAKNdLHr32Df6G8iaoaOx6pHaoiacwp26DaslxZHCGbibZhhCGven4rvmWP60GahtzgFjgCjR/0, createdBy=6b111703011, createdName=有备才能无患, createdTime=Fri Feb 23 21:01:26 CST 2018, time=2018-02-23, status=1, ipAttribution=)]
    2018-02-23 有备才能无患

    NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚.

    0

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    2018-02-23 有备才能无患

    NR4A核受体亚家族成员在造血细胞发育过程中发挥复杂的.相互重复的作用.此外还具有对血液恶性肿瘤的抑制作用.既往研究认为NR4A1和NR4A3在AML发展中.肿瘤抑制作用相互重叠.但其在造血干细胞(HSC)稳态中的作用尚未完全清楚.

    0