Cell：p53可抑制黑色素瘤的形成
生物谷报道：因具有防护癌症所致DNA损伤能力而被称为“基因组的守护人”的蛋白有一种完全不同的防护癌症的方式：通过刺激皮肤适应阳光下的紫外线变黑来抑制黑色素瘤形成，黑色素瘤是世界上增加最快的癌症类型。在
这项研究资深作者，Dana-Farber黑色素瘤研究项目主任，波士顿儿童医院儿科教授David E. Fisher博士说：“黑色素瘤的危险因素之一是不能变黑；那些很容易晒黑或色素沉着的人有较小概率发生黑色素瘤。研究表明p53，我们已知的一种抑癌蛋白，在保护我们皮肤免受阳光损伤中有重要作用。” 在去年发表的研究，Fisher和同事发现太阳发出的紫外线可以引起一种叫做角质化细胞的皮肤细胞产生和分泌一种激素——alpha-促黑色素细胞激素，这种激素贴附到黑色素细胞，刺激黑色素细胞产生使皮肤变黑的色素——黑色素。但是角质化细胞产生alpha-促黑色素细胞激素的过程仍然是个谜。研究者知道alpha-促黑色素细胞激素是在另一个蛋白阿片促黑激素皮质素原分解时产生的，也知道人们暴露在紫外线下时细胞内的阿片促黑激素皮质素原含量迅猛增加，但是不知道是什么引起阿片促黑激素皮质素原增加。一个可能的物质是p53。Fisher和同事检查了促进阿片促黑激素皮质素原蛋白产生的基因片段，发现这段基因与p53相连，这暗示p53连接到那里可加速阿片促黑激素皮质素原的产生。其他证据也证明这一点：研究人员将人和小鼠的角质化细胞暴露于紫外线下，6小时后，阿片促黑激素皮质素原和p53的含量均高于正常水平，alpha-促黑色素细胞激素是正常的30倍。进一步研究证实了p53在晒黑中的作用。研究者将p53插入到角质化细胞中，阿片促黑激素皮质素原含量明显增加。而将角质化细胞缺乏p53的小鼠置于紫外线下，阿片促黑激素皮质素原产生并不增加，小鼠也不被晒黑。研究的意义已超出了皮肤晒黑。一个常见的皮肤问题，尤其在中老年人中，是与日光照射无关的小的黑斑的出现。这些黑斑在大量细胞由于反复压力或皮肤受到刺激产生色素时出现。尽管这些没有危险，但由于黑斑存在的部位，这个问题成为影响美容的问题。
Fisher说：“我们的研究为炎症后色素沉着或老年班是如何产生的提供了一个可能的解释。我们知道这是压力的后果，而p53是一个典型的压力蛋白，在细胞遭受压力相关DNA损伤立刻起效。我们已有的p53知识表明它可能加速色素沉着过程。” 有可能p53以一种继发的先前未怀疑的方式来防护皮肤损伤。这种蛋白不仅使皮肤变黑，而且还影响人们享受阳光的欲望。阿片促黑激素皮质素原产生alpha-促黑色素细胞激素的过程也产生β内啡呔，β内啡呔可与体内阿片受体结合与愉悦情绪有关。Fisher说：“在日光下p53使皮肤变黑的同时也会影响神经回路，这些蛋白可能在调节晒黑与情绪之间提供了一种外在的联系。这就提出一个问题：是否p53介导的β内啡呔的产生参与了追寻阳光行为，这可能增加皮肤癌风险。”
Figure 1. POMC Is Induced by UV or p53 Overexpression
(A and B) Human primary keratinocytes (HPK) and PAM212 cells were irradiated with UV as described in Experimental Procedures. RNA and protein were collected at time 0 and at different time points after irradiation as indicated. The left panels represent POMC RNA levels as measured by quantitative RT-PCR and normalized to GAPDH. Results are expressed as the mean of the experiment done in triplicate ± the standard error of the mean (SEM). Induction is calculated relative to POMC levels in untreated cells. POMC and p53 protein levels, which were analyzed by western blot, are shown on the right along with α-tubulin, which served as loading control.
(C) PAM212 cells were transfected with either empty pcDNA plasmid, HA-p53 plasmid, or no plasmid. POMC RNA levels were measured by quantitative RT-PCR and normalized to GAPDH. Results are expressed as the mean of the experiment done in triplicate ± the SEM. POMC and p53 protein expression were analyzed by western blot, and α-tubulin was used as a loading control.
原文出处：
Cell Volume 128, Issue 5, Pages 803-1014 (9 March 2007)
Central Role of p
Pages 853-864
Rutao Cui, Hans R. Widlund, Erez Feige, Jennifer Y. Lin, Dara L. Wilensky, Viven E. Igras, John D'Orazio, Claire Y. Fung, Carl F. Schanbacher, Scott R. Granter and David E. Fisher
SummaryPlus | Full Text + Links | PDF (2041 K)
相关基因：
Official Symbol: POMC and Name: proopiomelanocortin (adrenocorticotropin/ beta-lipotropin/ alpha-melanocyte stimulating hormone/ beta-melanocyte stimulating hormone/ beta-endorphin) [Homo sapiens]
Other Aliases: ACTH, CLIP, LPH, MSH, NPP, POC
Other Designations: adrenocorticotropic hormone; adrenocorticotropin; alpha-MSH; alpha-melanocyte-stimulating hormone; beta-LPH; beta-MSH; beta-endorphin; beta-melanocyte-stimulating hormone; corticotropin; corticotropin-like intermediary peptide; corticotropin-lipotrophin; gamma-LPH; gamma-MSH; lipotropin beta; lipotropin gamma; melanotropin alpha; melanotropin beta; melanotropin gamma; met-enkephalin; pro-ACTH-endorphin; pro-opiomelanocortin; proopiomelanocortin
Chromosome: 2; Location: 2p23.3
MIM: 176830
GeneID: 5443
Official Symbol: Tp53 and Name: tumor protein p53 (Li-Fraumeni syndrome) [Homo sapiens]
Other Aliases: LFS1, TRP53, p53
Other Designations: p53 tumor suppressor; tumor protein p53
Chromosome: 17; Location: 17p13.1
MIM: 191170
GeneID: 7157
作者简介：
David E. Fisher, MD, PhD
Professor of Pediatrics,
Department
Centers/Programs:
Our laboratory studies molecular mechanisms regulating gene expression and development, as a means of understanding cancer biology and devising novel approaches to prevention, diagnosis, and treatment.
Research projects focus largely on the biology of melanocytes (pigment cells), the cells of origin of malignant melanoma, which is one of the most aggressive and treatment-resistant cancers in humans. We have extensively studied a transcription factor called Mitf, which is essential for the development of normal melanocytes and the survival of most melanomas. Mitf regulates both normal processes, such as pigmentation, and abnormal events, such as cancerous transformation. Numerous efforts are under way to understand how Mitf functions and to use this information for the design of improved clinical strategies for melanoma.
Another area of major research attention is the recent discovery that a collection of nonmelanoma solid tumors share extensive mechanistic features with melanoma. These tumors include alveolar soft part sarcoma, clear cell sarcoma, papillary renal cell carcinoma, and others. Our laboratory is studying these cancers through examination of the oncogenic transcription factors that drive their growth and survival. Major clues to therapeutic approaches are likely to come from the shared analysis of these seemingly diverse diseases.
Finally, through an understanding of the pathways which regulate normal melanocyte development, we are attempting to identify novel strategies aimed at prevention of skin cancer.
Doris Duke Distinguished Clinical Investigator Award, 2005
Endowed Investigatorship, Dana-Farber Cancer Institute, 2000
Faculty Teaching Award, Graduate Program at
Gertrude Elion Award for Cancer Research (AACR), 1998
Pew Foundation Scholars Award, 1995
McDonnell Foundation Research Scholar, 1995
Dr. Fisher received his PhD from
Argani P, Lae M, Hutchinson B, Reuter VE, Collins MH, Perentesis J, Tomaszewski JE, Brooks JS, Acs G, Bridge JA, Vargas SO, Davis IJ, Fisher DE, Ladanyi M. Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 2005;29:230-40.
Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005;436:117-22.
Miller AJ, Levy C,
Nishimura, EK, Granter, S, Fisher, DE. Mechanisms of hair graying: incomplete self-maintenance of melanocyte stem cells in the niche. Science 2005;307:720-4.
Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, Berghmans S, Mayhall EA, Traver D, Fletcher CD, Aster JC, Granter SR, Look AT, Lee C, Fisher DE, Zon LI. BRAF mutations are sufficient to promote nevus formation, and cooperate with p
Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 2004;6:565-76.
Miller AJ, Du J, Rowan S, Hershey CL, Widlund HR, Fisher DE. Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma. Cancer Res 2004;64:509-16.
Davis IJ, Bae-Li H, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez-Atayde AR, Argani P, Ladanyi M, Fletcher JA, Fisher DE. Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Proc Natl Acad Sci U S A 2003;100:6051-6.
Du J, Miller AJ, Widlund HR, Horstmann MA, Ramaswamy S, Fisher DE. MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. Am J Pathol 2003;163:333-43.
Huber WE, Price ER, Widlund HR, Du J, Davis IJ, Wegner M, Fisher DE. A tissue restricted cAMP transcriptional response: SOX10 modulates MSH-triggered expression of MITF in melanocytes. J Biol Chem 2003;278:45224-30.
相关报道：
Nature Genetics:研究者发现Slug基因是黑色素瘤恶性的关键
Molecular Cell：深入探究p53抑制肿瘤的内在机制
Cell：研究发现restore p53的肿瘤疗法具有风险性
- 众说风云 (已有1条评论)
