CONTRASTING ROLES FOR MYC AND MAD PROTEINS IN CELLULAR GROWTH AND DIFFERENTIATION
CONTRASTING ROLES FOR MYC AND MAD PROTEINS IN CELLULAR GROWTH AND DIFFERENTIATION
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DOI：
10.1073/pnas.92.18.8488
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发表时间：
1995-08-29
影响因子：
11.1
通讯作者：
DEPINHO, RA
中科院分区：
文献类型：
--
作者：
CHIN, L;SCHREIBERAGUS, N;DEPINHO, RA
Myc对细胞生长和基因表达的积极作用被Myc超家族的另一个成员Mad的活性所拮抗。在结构水平上对人mad的小鼠同源物的表征显示，先前显示的在人蛋白中用于抗Myc抑制、序列特异性DNA结合活性和与其伴侣Max的二聚化所需的结构域是高度保守的。在生物学水平上的保守性也是明显的，因为人和小鼠mad都可以拮抗c-myc与ras在培养细胞恶性转化中合作的能力。对发育中的小鼠c-myc和mad基因表达的分析显示，在组织分布和发育阶段方面存在着相反的模式。表达的区域差异在细胞水平上更引人注目，特别是在小鼠和人的胃肠道系统中，其中c-Myc蛋白很容易在结肠隐窝基部的未成熟增殖细胞中检测到，而Mad蛋白分布仅限于隐窝顶端的有丝分裂后分化细胞。在皮肤复层鳞状上皮的更分化的角膜下层中，Mad的梯度增加也很明显。总之，这些观察结果支持这样的观点，即Myc的下调和Mad的积累对于前体细胞向生长停滞的终末分化状态的进展可能是必要的。
The positive effects of Myc on cellular growth and gene expression are antagonized by activities of another member of the Myc superfamily, Mad. Characterization of the mouse homolog of human mad on the structural level revealed that domains shown previously to be required in the human protein for anti-Myc repression, sequence-specific DNA-binding activity, and dimerization with its partner Max are highly conserved. Conservation is also evident on the biological level in that both human and mouse mad can antagonize the ability of c-myc to cooperate with ras in the malignant transformation of cultured cells. An analysis of c-myc and mad gene expression in the developing mouse showed contrasting patterns with respect to tissue distribution and developmental stage. Regional differences in expression were more striking on the cellular level, particularly in the mouse and human gastrointestinal system, wherein c-Myc protein was readily detected in immature proliferating cells at the base of the colonic crypts, while Mad protein distribution was restricted to the postmitotic differentiated cells in the apex of the crypts. An increasing gradient of Mad was also evident in the more differentiated subcorneal layers of the stratified squamous epithelium of the skin. Together, these observations support the view that both downregulation of Myc and accumulation of Mad may be necessary for progression of precursor cells to a growth-arrested, terminally differentiated state.