生物谷報(bào)道：因具有防護(hù)癌癥所致DNA損傷能力而被稱為“基因組的守護(hù)人”的蛋白有一種完全不同的防護(hù)癌癥的方式：通過刺激皮膚適應(yīng)陽光下的紫外線變黑來抑制黑色素瘤形成,，黑色素瘤是世界上增加最快的癌癥類型,。在3月9日細(xì)胞雜志的一篇文章中,，Dana-Farber癌癥研究所的研究人員報(bào)告，p53蛋白不僅與皮膚曬黑有關(guān),，而且在人們希望享受陽光的欲望中起作用,。促進(jìn)皮膚變黑能降低發(fā)生黑色素瘤的危險(xiǎn)度。
這項(xiàng)研究資深作者,，Dana-Farber黑色素瘤研究項(xiàng)目主任,，波士頓兒童醫(yī)院兒科教授David E. Fisher博士說：“黑色素瘤的危險(xiǎn)因素之一是不能變黑；那些很容易曬黑或色素沉著的人有較小概率發(fā)生黑色素瘤,。研究表明p53,，我們已知的一種抑癌蛋白，在保護(hù)我們皮膚免受陽光損傷中有重要作用,。” 在去年發(fā)表的研究,，F(xiàn)isher和同事發(fā)現(xiàn)太陽發(fā)出的紫外線可以引起一種叫做角質(zhì)化細(xì)胞的皮膚細(xì)胞產(chǎn)生和分泌一種激素——alpha-促黑色素細(xì)胞激素，這種激素貼附到黑色素細(xì)胞,，刺激黑色素細(xì)胞產(chǎn)生使皮膚變黑的色素——黑色素,。但是角質(zhì)化細(xì)胞產(chǎn)生alpha-促黑色素細(xì)胞激素的過程仍然是個(gè)謎。研究者知道alpha-促黑色素細(xì)胞激素是在另一個(gè)蛋白阿片促黑激素皮質(zhì)素原分解時(shí)產(chǎn)生的,，也知道人們暴露在紫外線下時(shí)細(xì)胞內(nèi)的阿片促黑激素皮質(zhì)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質(zhì)素原增加。一個(gè)可能的物質(zhì)是p53,。Fisher和同事檢查了促進(jìn)阿片促黑激素皮質(zhì)素原蛋白產(chǎn)生的基因片段,，發(fā)現(xiàn)這段基因與p53相連，這暗示p53連接到那里可加速阿片促黑激素皮質(zhì)素原的產(chǎn)生,。其他證據(jù)也證明這一點(diǎn)：研究人員將人和小鼠的角質(zhì)化細(xì)胞暴露于紫外線下,，6小時(shí)后，阿片促黑激素皮質(zhì)素原和p53的含量均高于正常水平,，alpha-促黑色素細(xì)胞激素是正常的30倍,。進(jìn)一步研究證實(shí)了p53在曬黑中的作用。研究者將p53插入到角質(zhì)化細(xì)胞中,，阿片促黑激素皮質(zhì)素原含量明顯增加,。而將角質(zhì)化細(xì)胞缺乏p53的小鼠置于紫外線下，阿片促黑激素皮質(zhì)素原產(chǎn)生并不增加,，小鼠也不被曬黑,。研究的意義已超出了皮膚曬黑。一個(gè)常見的皮膚問題,，尤其在中老年人中,，是與日光照射無關(guān)的小的黑斑的出現(xiàn)。這些黑斑在大量細(xì)胞由于反復(fù)壓力或皮膚受到刺激產(chǎn)生色素時(shí)出現(xiàn)。盡管這些沒有危險(xiǎn),，但由于黑斑存在的部位,，這個(gè)問題成為影響美容的問題。
Fisher說：“我們的研究為炎癥后色素沉著或老年班是如何產(chǎn)生的提供了一個(gè)可能的解釋,。我們知道這是壓力的后果,，而p53是一個(gè)典型的壓力蛋白，在細(xì)胞遭受壓力相關(guān)DNA損傷立刻起效,。我們已有的p53知識(shí)表明它可能加速色素沉著過程,。” 有可能p53以一種繼發(fā)的先前未懷疑的方式來防護(hù)皮膚損傷。這種蛋白不僅使皮膚變黑,，而且還影響人們享受陽光的欲望,。阿片促黑激素皮質(zhì)素原產(chǎn)生alpha-促黑色素細(xì)胞激素的過程也產(chǎn)生β內(nèi)啡呔，β內(nèi)啡呔可與體內(nèi)阿片受體結(jié)合與愉悅情緒有關(guān),。Fisher說：“在日光下p53使皮膚變黑的同時(shí)也會(huì)影響神經(jīng)回路,，這些蛋白可能在調(diào)節(jié)曬黑與情緒之間提供了一種外在的聯(lián)系。這就提出一個(gè)問題：是否p53介導(dǎo)的β內(nèi)啡呔的產(chǎn)生參與了追尋陽光行為,，這可能增加皮膚癌風(fēng)險(xiǎn),。”
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.
原文出處：
Cell Volume 128, Issue 5, Pages 803-1014 (9 March 2007)
Central Role of p53 in the Suntan Response and Pathologic Hyperpigmentation • ARTICLE
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)
相關(guān)基因：
POMC
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
TP53
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
作者簡介：
David E. Fisher, MD, PhD
Professor of Pediatrics, Harvard Medical School
Department
Pediatric Oncology
Centers/Programs:
Pediatric/Jimmy Fund Clinic
Cutaneous Cancer
Research
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.
Recent Awards
Doris Duke Distinguished Clinical Investigator Award, 2005
Endowed Investigatorship, Dana-Farber Cancer Institute, 2000
Faculty Teaching Award, Graduate Program at Harvard Medical School, 1999
Gertrude Elion Award for Cancer Research (AACR), 1998
Pew Foundation Scholars Award, 1995
McDonnell Foundation Research Scholar, 1995
Biography
Dr. Fisher received his PhD from Rockefeller University in 1984, and his MD from Cornell University in 1985. Following his residency in internal medicine at Massachusetts General Hospital, he completed clinical fellowships in both adult and pediatric oncology at DFCI, followed by postdoctoral research at the Massachusetts Institute of Technology. He joined DFCI in 1991.
select Publications
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, Davis IJ, Razin E, Fisher DE. Sumoylation of MITF and its related family members TFE3 and TFEB. J Biol Chem 2005;280:146-55.
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 p53 in the genesis of melanoma. Curr Biol 2005;15:249-54.
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.
