TGF-BETA REGULATION OF EPITHELIAL-CELL PROLIFERATION
TGF-BETA REGULATION OF EPITHELIAL-CELL PROLIFERATION
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DOI：
10.1002/mrd.1080320215
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发表时间：
1992-06-01
影响因子：
2.5
通讯作者：
MOSES, HL
中科院分区：
文献类型：
--
作者：
MOSES, HL
转化生长因子-β1对细胞增殖的主要作用是抑制作用。早期的研究表明，转化生长因子-β1抑制皮肤角质形成细胞的增殖涉及c-myc转录的抑制，间接证据表明视网膜母细胞瘤基因的蛋白产物可能参与了这一过程。经SV40和HPV-16或HPV-18转化的皮肤角质形成细胞能抵抗转化生长因子-β对c-myc mRNA的抑制和生长抑制。HPV-16E7基因、腺病毒EIA和SV40大T抗原(Tag)的瞬时表达阻断了转化生长因子-β1对c-myc转录的抑制。对EIA和TAG转化缺陷突变体的研究表明，一种与肿瘤病毒癌蛋白的保守结构域相互作用的细胞蛋白(S)介导转化生长因子-β1抑制c-myc转录和角质形成细胞的生长。PRB在皮肤角质形成细胞中的瞬时表达抑制了人c-myc启动子/CAT的转录，与转化生长因子-β1一样有效。同样的c-myc启动子区域，被称为转化生长因子-β调控元件(TCE)，是转化生长因子-β-1和pRb共同调控所必需的。TCE结合了大约106 kDa的细胞蛋白，这种结合被转化生长因子-β1处理后减少。我们的结果表明，pRb可以抑制c-myc的转录，提示除pRb外，还有细胞因子(S)参与了转化生长因子-β1途径，从而抑制了c-myc的转录和生长抑制。PRb可能参与了抑制c-myc转录的转化生长因子-β1途径，c-myc是一种细胞原癌基因，参与正向调节细胞增殖。因此，转化生长因子-β-1可能通过肿瘤抑制基因产物pRb负向调节c-myc转录，进而调节细胞生长。这将在扩散性生长抑制物的反应途径中涉及肿瘤抑制基因，可能类似于核原癌基因参与生长因子途径。
The predominant effect of TGF-beta-1 on cell proliferation is inhibition. Earlier studies demonstrated that TGF-beta-1 inhibition of skin keratinocyte proliferation involves suppression of c-myc transcription and indirect evidence suggested that the protein product of the retinoblastoma gene (pRB) may be involved in this process. Skin keratinocytes transformed by SV40 and human papilloma virus-16 (HPV-16) or HPV-18 resisted growth inhibition and suppression of c-myc mRNA by TGF-beta. Transient expression of HPV-16 E7 gene, adenovirus EIA, and SV40 large T antigen (TAg) blocked the TGF-beta-1 suppression of c-myc transcription. Studies with transformation-defective mutants of EIA and TAg suggested that a cellular protein(s) that interacts with a conserved domain of the DNA tumor virus oncoproteins mediates TGF-beta-1 suppression of c-myc transcription and keratinocyte growth. Transient expression of pRB in skin keratinocytes repressed human c-myc promoter/CAT transcription as effectively as TGF-beta-1. The same c-myc promoter region, termed the TGF-beta Control Element (TCE), was required for regulation by both TGF-beta-1 and pRB. TCE bound a cellular protein of approximately 106 kDa and this binding was decreased by TGF-beta-1 treatment. Our data indicate that pRB can inhibit c-myc transcription and suggest the involvement of cellular factor(s) in addition to pRB in the TGF-beta-1 pathway for the suppression of c-myc transcription and growth inhibition. The possible involvement of pRB in the TGF-beta-1 pathway for suppression of c-myc transcription has a number of implications; c-myc is a cellular proto-oncogene involved in positively regulating cell proliferation. TGF-beta-1 may therefore act through the tumor suppressor gene product, pRB, to negatively regulate c-myc transcription and subsequently cell growth. This would implicate tumor suppressor genes in the response pathway for diffusible growth inhibitors, perhaps analogous to nuclear proto-oncogene involvement in the growth factor pathway.