Box Neil F, Terzian Tamara
Department of Dermatology, University of Colorado at Denver, Aurora, CO, USA.
Pigment Cell Melanoma Res. 2008 Oct;21(5):525-33. doi: 10.1111/j.1755-148X.2008.00495.x. Epub 2007 Aug 6.
p53 has a central role in skin pigmentation and may impact on melanoma at all stages, however, as it's mutation frequency in melanoma is low, it's role has been somewhat under-appreciated. During normal skin function, p53 in the keratinocyte is a transducer of the skin tanning signal and an essential component of what is effectively a keratinocyte-melanocyte signaling cycle that regulates skin pigmentation. It is clear that this cycle functions optimally in skin of dark pigmentation. When melanin biosynthesis is genetically disrupted in skin of white complexion, we propose that this cycle operates as a promoter of melanocyte proliferation. The cell autonomous function of p53 in melanocytes is not well described, however, the balance of the evidence suggests that p53 is an effective tumor suppressor and the myriad of mechanisms by which the p53 pathway may be dysregulated in tumors attests to it importance as a tumor suppressor. In this review, we outline the known mechanisms that impair p53 itself and its immediate regulators or target genes during melanomagenesis. Due to the importance of this pathway, it is clear that p53 disruptions may relate directly to a patient's prognosis. This pathway will continue to be a focus of investigation, particularly with respect to targeted experimental chemotherapeutics.
p53在皮肤色素沉着中起核心作用，可能在黑色素瘤的各个阶段都有影响，然而，由于其在黑色素瘤中的突变频率较低，其作用在一定程度上未得到充分重视。在正常皮肤功能中，角质形成细胞中的p53是皮肤晒黑信号的转导者，也是有效调节皮肤色素沉着的角质形成细胞-黑素细胞信号循环的重要组成部分。很明显，这个循环在深色皮肤中功能最佳。当白色皮肤的黑色素生物合成在基因上受到干扰时，我们认为这个循环作为黑素细胞增殖的促进因子发挥作用。p53在黑素细胞中的细胞自主功能尚未得到很好的描述，然而，证据的平衡表明p53是一种有效的肿瘤抑制因子，并且p53途径在肿瘤中可能失调的众多机制证明了其作为肿瘤抑制因子的重要性。在这篇综述中，我们概述了在黑色素瘤发生过程中损害p53本身及其直接调节因子或靶基因的已知机制。由于这条途径的重要性，很明显p53的破坏可能与患者的预后直接相关。这条途径将继续成为研究的重点，特别是在靶向实验性化疗方面。
