The RASSF family of proteins has been extensively studied in terms of their genetics, structure and function. One of the functions that has been increasingly studied is the role of the RASSF proteins in the DNA damage response. Surprisingly, this research, which encompasses both the classical and N-terminal RASSF proteins, has revealed an involvement of the RASSFs in oncogenic pathways as well as the more familiar tumour suppressor pathways usually associated with the RASSF family members. The most studied protein with respect to DNA damage is RASSF1A, which has been shown, not only to be activated by ATM, a major regulator of the DNA damage response, but also to bind to and activate a number of different pathways which all lead to and feedback from the guardian of the genome, p53. In this review we discuss the latest research linking the RASSF proteins to DNA damage signalling and maintenance of genomic integrity and look at how this knowledge is being utilised in the clinic to enhance the effectiveness of traditional cancer therapies such as radiotherapy. 1. Introduction RASSF proteins were originally designated on the basis of sequence homology to domains that associate with Ras-like small GTP-binding proteins. These domains are known as Ras association (RA) domains [RalGDS (Ral guanine nucleotide dissociation stimulator)/AF6 (ALL-1 fusion partner from chromosome 6)] and are distinct from Ras-binding domains (RBD) which bind an alternative set of Ras effectors [1, 2]. Ras belongs to a family of small G-proteins that are ubiquitously expressed and oscillate between an inactive, GDP-bound state, and an active, GTP-bound state, in response to diverse cellular signals. Various GTP-bound Ras-like proteins bind effector proteins to mediate distinct biological responses. There are 150 Ras-like proteins encoded in the human genome which can be grouped by homology or functionality, as being similar to Ras, Rho, Rab, Arf (ADP-ribosylation factor), or Ran. While originally suggested to associate with Ras [3], the RASSF family has a differential affinity for Ras-like GTPases, with NORE1 (RAPL/RASSF5) displaying a much greater affinity for the closely related Ras homolog, Rap1B, than H-Ras itself [4]. The RA domain of RASSF1 associates with K-Ras, rather than H-Ras or N-Ras and is also described to associate with Ran [5, 6]. There are now 10 members in the RASSF family (RASSF1-10) subdivided into two distinct subgroups, the classical RASSF proteins (RASSF1-6) and the N-terminal RASSF proteins (RASSF7-10) based on the location of the RA domain [7]. Little is known
References
[1]
C. P. Ponting and D. R. Benjamin, “A novel family of Ras-binding domains,” Trends in Biochemical Sciences, vol. 21, no. 11, pp. 422–425, 1996.
[2]
T. Yamamoto, S. Taya, and K. Kaibuchi, “Ras-induced transformation and signaling pathway,” Journal of Biochemistry, vol. 126, no. 5, pp. 799–803, 1999.
[3]
D. Vavvas, X. Li, J. Avruch, and X. F. Zhang, “Identification of Nore1 as a potential Ras effector,” Journal of Biological Chemistry, vol. 273, no. 10, pp. 5439–5442, 1998.
[4]
S. Wohlgemuth, C. Kiel, A. Kr？mer, L. Serrano, F. Wittinghofer, and C. Herrmann, “Recognizing and defining true ras binding domains I: biochemical analysis,” Journal of Molecular Biology, vol. 348, no. 3, pp. 741–758, 2005.
[5]
A. Dallol, L. B. Hesson, D. Matallanas et al., “RAN GTPase is a RASSF1A effector involved in controlling microtubule organization,” Current Biology, vol. 19, no. 14, pp. 1227–1232, 2009.
[6]
D. Matallanas, D. Romano, F. Al-Mulla et al., “Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras,” Molecular Cell, vol. 44, no. 6, pp. 893–906, 2011.
[7]
V. Sherwood, R. Manbodh, C. Sheppard, and A. D. Chalmers, “RASSF7 is a member of a new family of RAS association domain-containing proteins and is required for completing mitosis,” Molecular Biology of the Cell, vol. 19, no. 4, pp. 1772–1782, 2008.
[8]
E. Hwang, K. S. Ryu, K. P？？kk？nen et al., “Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 22, pp. 9236–9241, 2007.
[9]
H. Scheel and K. Hofmann, “A novel interaction motif, SARAH, connects three classes of tumor suppressor,” Current Biology, vol. 13, no. 23, pp. R899–R900, 2003.
[10]
G. Grigoryan and A. E. Keating, “Structural specificity in coiled-coil interactions,” Current Opinion in Structural Biology, vol. 18, no. 4, pp. 477–483, 2008.
[11]
A. C. Newton, “Protein kinase C: seeing two domains,” Current Biology, vol. 5, no. 9, pp. 973–976, 1995.
[12]
E. Harjes, S. Harjes, S. Wohlgemuth et al., “GTP-Ras disrupts the intramolecular complex of C1 and RA domains of nore1,” Structure, vol. 14, no. 5, pp. 881–888, 2006.
[13]
G. Hamilton, K. S. Yee, S. Scrace, and E. O'Neill, “ATM regulates a RASSF1A-dependent DNA damage response,” Current Biology, vol. 19, no. 23, pp. 2020–2025, 2009.
[14]
J. Hung, Y. Kishimoto, K. Sugio et al., “Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma,” Journal of the American Medical Association, vol. 273, no. 24, p. 1908, 1995.
[15]
K. Kok, S. L. Naylor, and C. H. C. M. Buys, “Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes,” Advances in Cancer Research, vol. 71, pp. 27–92, 1997.
[16]
Y. Sekido, M. Ahmadian, I. I. Wistuba et al., “Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene,” Oncogene, vol. 16, no. 24, pp. 3151–3157, 1998.
[17]
V. Sundaresan, S. P. Ganly, P. Hasleton et al., “p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus,” Oncogene, vol. 7, no. 10, pp. 1989–1997, 1992.
[18]
I. I. Wistuba, C. Behrens, S. Milchgrub et al., “Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma,” Oncogene, vol. 18, no. 3, pp. 643–650, 1999.
[19]
I. I. Wistuba, C. Behrens, A. K. Virmani et al., “High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints,” Cancer Research, vol. 60, no. 7, pp. 1949–1960, 2000.
[20]
Y. Sekido, K. M. Fong, and J. D. Minna, “Progress in understanding the molecular pathogenesis of human lung cancer,” Biochimica et Biophysica Acta, vol. 1378, no. 1, pp. F21–F59, 1998.
[21]
M. I. Lerman and J. D. Minna, “The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes,” Cancer Research, vol. 60, no. 21, pp. 6116–6133, 2000.
[22]
R. Dammann, C. Li, J. H. Yoon, P. L. Chin, S. Bates, and G. P. Pfeifer, “Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3,” Nature Genetics, vol. 25, no. 3, pp. 315–319, 2000.
[23]
H. Donninger, M. D. Vos, and G. J. Clark, “The RASSF1A tumor suppressor,” Journal of Cell Science, vol. 120, no. 18, pp. 3163–3172, 2007.
[24]
L. B. Hesson, W. N. Cooper, and F. Latif, “The role of RASSF1A methylation in cancer,” Disease Markers, vol. 23, no. 1-2, pp. 73–87, 2007.
[25]
P. A. Jones and S. B. Baylin, “The epigenomics of cancer,” Cell, vol. 128, no. 4, pp. 683–692, 2007.
[26]
R. K. Palakurthy, N. Wajapeyee, M. K. Santra et al., “Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression,” Molecular Cell, vol. 36, no. 2, pp. 219–230, 2009.
[27]
L. van der Weyden and D. J. Adams, “The Ras-association domain family (RASSF) members and their role in human tumourigenesis,” Biochimica et Biophysica Acta, vol. 1776, no. 1, pp. 58–85, 2007.
[28]
A. M. Richter, G. P. Pfeifer, and R. H. Dammann, “The RASSF proteins in cancer; from epigenetic silencing to functional characterization,” Biochimica et Biophysica Acta, vol. 1796, no. 2, pp. 114–128, 2009.
[29]
D. G. Burbee, E. Forgacs, S. Z？chbauer-Müller et al., “Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression,” Journal of the National Cancer Institute, vol. 93, no. 9, pp. 691–699, 2001.
[30]
K. Dreijerink, E. Braga, I. Kuzmin et al., “The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7504–7509, 2001.
[31]
I. Kuzmin, J. W. Gillespie, A. Protopopov et al., “The RASSF1A tumor suppressor gene is inactivated in prostate tumors and suppresses growth of prostate carcinoma cells,” Cancer Research, vol. 62, no. 12, pp. 3498–3502, 2002.
[32]
C. Balch, P. Yan, T. Craft et al., “Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer,” Molecular Cancer Therapeutics, vol. 4, no. 10, pp. 1505–1514, 2005.
[33]
S. Tommasi, R. Dammann, Z. Zhang et al., “Tumor susceptibility of Rassf1a knockout mice,” Cancer Research, vol. 65, no. 1, pp. 92–98, 2005.
[34]
L. Van Der Weyden, K. K. Tachibana, M. A. Gonzalez et al., “The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis,” Molecular and Cellular Biology, vol. 25, no. 18, pp. 8356–8367, 2005.
[35]
S. Tommasi, A. Besaratinia, S. P. Wilczynski, and G. P. Pfeifer, “Loss of Rassf1a enhances p53-mediated tumor predisposition and accelerates progression to aneuploidy,” Oncogene, vol. 30, no. 6, pp. 690–700, 2011.
[36]
L. Liu, C. Guo, R. Dammann, S. Tommasi, and G. P. Pfeifer, “RASSF1A interacts with and activates the mitotic kinase Aurora-A,” Oncogene, vol. 27, no. 47, pp. 6175–6186, 2008.
[37]
R. Rong, L. Y. Jiang, M. S. Sheikh, and Y. Huang, “Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation,” Oncogene, vol. 26, no. 55, pp. 7700–7708, 2007.
[38]
M. S. Song, S. J. Song, S. J. Kim, K. Nakayama, K. I. Nakayama, and D. S. Lim, “Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1-S transition,” Oncogene, vol. 27, no. 22, pp. 3176–3185, 2008.
[39]
S. J. Song, S. J. Kim, M. S. Song, and D. S. Lim, “Aurora B-mediated phosphorylation of RASSF1A maintains proper cytokinesis by recruiting syntaxin16 to the midzone and midbody,” Cancer Research, vol. 69, no. 22, pp. 8540–8544, 2009.
[40]
S. J. Song, M. S. Song, S. J. Kim et al., “Aurora a regulates prometaphase progression by inhibiting the ability of RASSF1A to suppress APC-Cdc20 activity,” Cancer Research, vol. 69, no. 6, pp. 2314–2323, 2009.
[41]
D. Durocher and S. P. Jackson, “DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?” Current Opinion in Cell Biology, vol. 13, no. 2, pp. 225–231, 2001.
[42]
S. T. Kim, D. S. Lim, C. E. Canman, and M. B. Kastan, “Substrate specificities and identification of putative substrates of ATM kinase family members,” Journal of Biological Chemistry, vol. 274, no. 53, pp. 37538–37543, 1999.
[43]
L. Shivakumar, J. Minna, T. Sakamaki, R. Pestell, and M. A. White, “The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation,” Molecular and Cellular Biology, vol. 22, no. 12, pp. 4309–4318, 2002.
[44]
H. Endoh, Y. Yatabe, S. Shimizu et al., “RASSF1A gene inactivation in non-small cell lung cancer and its clinical implication,” International Journal of Cancer, vol. 106, no. 1, pp. 45–51, 2003.
[45]
B. Gao, X. J. Xie, C. Huang et al., “RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers,” Cancer Research, vol. 68, no. 1, pp. 22–25, 2008.
[46]
J. Bergqvist, A. Latif, S. A. Roberts et al., “RASSF1A polymorphism in familial breast cancer,” Familial Cancer, vol. 9, no. 3, pp. 263–265, 2010.
[47]
C. J. Foley, H. Freedman, S. L. Choo et al., “Dynamics of RASSF1A/MOAP-1 association with death receptors,” Molecular and Cellular Biology, vol. 28, no. 14, pp. 4520–4535, 2008.
[48]
M. S. Song, S. J. Song, S. Y. Kim, H. J. Oh, and D. S. Lim, “The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex,” EMBO Journal, vol. 27, no. 13, pp. 1863–1874, 2008.
[49]
S. Baksh, S. Tommasi, S. Fenton et al., “The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to bax conformational change and cell death,” Molecular Cell, vol. 18, no. 6, pp. 637–650, 2005.
[50]
D. Michael and M. Oren, “The p53-Mdm2 module and the ubiquitin system,” Seminars in Cancer Biology, vol. 13, no. 1, pp. 49–58, 2003.
[51]
B. Vogelstein, D. Lane, and A. J. Levine, “Surfing the p53 network,” Nature, vol. 408, no. 6810, pp. 307–310, 2000.
[52]
Y. Haupt, R. Maya, A. Kazaz, and M. Oren, “Mdm2 promotes the rapid degradation of p53,” Nature, vol. 387, no. 6630, pp. 296–299, 1997.
[53]
M. H. G. Kubbutat, S. N. Jones, and K. H. Vousden, “Regulation of p53 stability by Mdm2,” Nature, vol. 387, no. 6630, pp. 299–303, 1997.
[54]
A. M. Bode and Z. Dong, “Post-translational modification of p53 in tumorigenesis,” Nature Reviews Cancer, vol. 4, no. 10, pp. 793–805, 2004.
[55]
R. Maya, M. Balass, S. T. Kim et al., “ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage,” Genes and Development, vol. 15, no. 9, pp. 1067–1077, 2001.
[56]
X. Yang, R. Khosravi-Far, H. Y. Chang, and D. Baltimore, “Daxx, a novel fas-binding protein that activates JNK and apoptosis,” Cell, vol. 89, no. 7, pp. 1067–1076, 1997.
[57]
Y. Tian, et al., “Tumor suppressor RASSF1A promoter: p53 binding and methylation,” PLoS One, vol. 6, no. 3, article e17017, 2011.
[58]
H. Glantschnig, G. A. Rodan, and A. A. Reszka, “Mapping of MST1 kinase sites of phosphorylation: activation and autophosphorylation,” Journal of Biological Chemistry, vol. 277, no. 45, pp. 42987–42996, 2002.
[59]
C. Guo, X. Zhang, and G. P. Pfeifer, “The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2,” Journal of Biological Chemistry, vol. 286, no. 8, pp. 6253–6261, 2011.
[60]
C. L. Creasy, D. M. Ambrose, and J. Chernoff, “The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain,” Journal of Biological Chemistry, vol. 271, no. 35, pp. 21049–21053, 1996.
[61]
J. Chernoff, “Cloning and characterization of a member of the MST subfamily of Ste20-like kinases,” Gene, vol. 167, no. 1-2, pp. 303–306, 1995.
[62]
C. L. Creasy and J. Chernoff, “Cloning and characterization of a human protein kinase with homology to Ste20,” Journal of Biological Chemistry, vol. 270, no. 37, pp. 21695–21700, 1995.
[63]
L. K. Taylor, H. C. R. Wang, and R. L. Erikson, “Newly identified stress-responsive protein kinases, Krs-1 and Krs-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 19, pp. 10099–10104, 1996.
[64]
J. Colombani, C. Polesello, F. Josué, and N. Tapon, “Dmp53 activates the hippo pathway to promote cell death in response to DNA damage,” Current Biology, vol. 16, no. 14, pp. 1453–1458, 2006.
[65]
W. Wen, F. Zhu, J. Zhang et al., “MST1 promotes apoptosis through phosphorylation of histone H2AX,” Journal of Biological Chemistry, vol. 285, no. 50, pp. 39108–39116, 2010.
[66]
F. Yuan, Q. Xie, J. Wu et al., “MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation,” Journal of Biological Chemistry, vol. 286, no. 9, pp. 6940–6945, 2011.
[67]
W. L. Cheung, K. Ajiro, K. Samejima et al., “Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase,” Cell, vol. 113, no. 4, pp. 507–517, 2003.
[68]
M. K. Lehtinen, Z. Yuan, P. R. Boag et al., “A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span,” Cell, vol. 125, no. 5, pp. 987–1001, 2006.
[69]
S. Ura, H. Nishina, Y. Gotoh, and T. Katada, “Activation of the c-Jun N-terminal kinase pathway by MST1 is essential and sufficient for the induction of chromatin condensation during apoptosis,” Molecular and Cellular Biology, vol. 27, no. 15, pp. 5514–5522, 2007.
[70]
M. Praskova, F. Xia, and J. Avruch, “MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation,” Current Biology, vol. 18, no. 5, pp. 311–321, 2008.
[71]
C. Guo, S. Tommasi, L. Liu, J. K. Yee, R. Dammann, and G. Pfeifer, “RASSF1A is part of a complex similar to the drosophila hippo/salvador/lats tumor-suppressor network,” Current Biology, vol. 17, no. 8, pp. 700–705, 2007.
[72]
E. E. O'Neill, D. Matallanas, and W. Kolch, “Mammalian sterile 20-like kinases in tumor suppression: an emerging pathway,” Cancer Research, vol. 65, no. 13, pp. 5485–5487, 2005.
[73]
B. V. V. G. Reddy and K. D. Irvine, “The fat and warts signaling pathways: new insights into their regulation, mechanism and conservation,” Development, vol. 135, no. 17, pp. 2827–2838, 2008.
[74]
B. Zhao, X. Wei, W. Li et al., “Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control,” Genes and Development, vol. 21, no. 21, pp. 2747–2761, 2007.
[75]
K. S. Yee and E. O'Neill, “YAP1: friend and foe,” Cell Cycle, vol. 9, no. 8, pp. 1447–1448, 2010.
[76]
S. Basu, N. F. Totty, M. S. Irwin, M. Sudol, and J. Downward, “Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis,” Molecular Cell, vol. 11, no. 1, pp. 11–23, 2003.
[77]
M. Dobbelstein, S. Strano, J. Roth, and G. Blandino, “p73-induced apoptosis: a question of compartments and cooperation,” Biochemical and Biophysical Research Communications, vol. 331, no. 3, pp. 688–693, 2005.
[78]
G. Melino, F. Bernassola, M. Ranalli et al., “p75 induces apoptosis via PUMA transactivation and bax mitochondrial translocation,” Journal of Biological Chemistry, vol. 279, no. 9, pp. 8076–8083, 2004.
[79]
D. Matallanas, D. Romano, K. Yee et al., “RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein,” Molecular Cell, vol. 27, no. 6, pp. 962–975, 2007.
[80]
S. Strano, O. Monti, N. Pediconi et al., “The transcriptional coactivator yes-associated protein drives p73 gene-target specificity in response to DNA damage,” Molecular Cell, vol. 18, no. 4, pp. 447–459, 2005.
[81]
H. Ke, J. Pei, Z. Ni et al., “Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL,” Experimental Cell Research, vol. 298, no. 2, pp. 329–338, 2004.
[82]
M. Kawahara, T. Hori, K. Chonabayashi, T. Oka, M. Sudol, and T. Uchiyama, “Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73,” Blood, vol. 112, no. 9, pp. 3856–3866, 2008.
[83]
Y. Aylon, N. Yabuta, H. Besserglick et al., “Silencing of the lats2 tumor suppressor overrides a p53-dependent oncogenic stress checkpoint and enables mutant H-Ras-driven cell transformation,” Oncogene, vol. 28, no. 50, pp. 4469–4479, 2009.
[84]
Y. Aylon, Y. Ofir-Rosenfeld, N. Yabuta et al., “The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1,” Genes and Development, vol. 24, no. 21, pp. 2420–2429, 2010.
[85]
A. M. Vigneron, R. L. Ludwig, and K. H. Vousden, “Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP,” Genes and Development, vol. 24, no. 21, pp. 2430–2439, 2010.
[86]
P. F. Langton, J. Colombani, E. H. Y. Chan, A. Wepf, M. Gstaiger, and N. Tapon, “The dASPP-dRASSF8 complex regulates cell-cell adhesion during drosophila retinal morphogenesis,” Current Biology, vol. 19, no. 23, pp. 1969–1978, 2009.
[87]
D. Pan, “The hippo signaling pathway in development and cancer,” Developmental Cell, vol. 19, no. 4, pp. 491–505, 2010.
[88]
Y. Aylon, D. Michael, A. Shmueli, N. Yabuta, H. Nojima, and M. Oren, “A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization,” Genes and Development, vol. 20, no. 19, pp. 2687–2700, 2006.
[89]
N. Okada, N. Yabuta, H. Suzuki, Y. Aylon, M. Oren, and H. Nojima, “A novel Chk1/2-Lats2-14-3-3 signaling pathway regulates P-body formation in response to UV damage,” Journal of Cell Science, vol. 124, no. 1, pp. 57–67, 2011.
[90]
M. Zagurovskaya, M. M. Shareef, A. Das et al., “EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells,” Oncogene, vol. 28, no. 8, pp. 1121–1131, 2009.
[91]
C. Polesello, S. Huelsmann, N. Brown, and N. Tapon, “The drosophila RASSF homolog antagonizes the hippo pathway,” Current Biology, vol. 16, no. 24, pp. 2459–2465, 2006.
[92]
H. Donninger, N. Allen, A. Henson et al., “Salvador protein is a tumor suppressor effector of RASSF1A with hippo pathway-independent functions,” Journal of Biological Chemistry, vol. 286, no. 21, pp. 18483–18491, 2011.
[93]
M. D. Vos, A. Martinez, C. Elam et al., “A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability,” Cancer Research, vol. 64, no. 12, pp. 4244–4250, 2004.
[94]
D. Kitagawa, H. Kajiho, T. Negishi et al., “Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation,” EMBO Journal, vol. 25, no. 14, pp. 3286–3297, 2006.
[95]
E. Escobar-Cabrera, D. K. W. Lau, S. Giovinazzi, A. M. Ishov, and L. P. McIntosh, “Structural characterization of the DAXX N-terminal helical bundle domain and its complex with Rassf1C,” Structure, vol. 18, no. 12, pp. 1642–1653, 2010.
[96]
X. Zhou, T.-T. Li, X. Feng et al., “Targeted polyubiquitylation of RASSF1C by the Mule and SCF β-TrCP ligases in response to DNA damage,” Biochemical Journal, vol. 441, no. 1, pp. 227–236, 2012.
[97]
Y. G. Amaar, M. G. Minera, L. K. Hatran, D. D. Strong, S. Mohan, and M. E. Reeves, “Ras association domain family 1C protein stimulates human lung cancer cell proliferation,” American Journal of Physiology, vol. 291, no. 6, pp. L1185–L1190, 2006.
[98]
M. E. Reeves, S. W. Baldwin, M. L. Baldwin et al., “Ras-association domain family 1C protein promotes breast cancer cell migration and attenuates apoptosis,” BMC Cancer, vol. 10, article 562, 2010.
[99]
R. Dammann, U. Schagdarsurengin, C. Seidel et al., “The tumor suppressor RASSF1A in human carcinogenesis: an update,” Histology and Histopathology, vol. 20, no. 2, pp. 645–663, 2005.
[100]
J. W. F. Catto, A. R. Azzouzi, I. Rehman et al., “Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma,” Journal of Clinical Oncology, vol. 23, no. 13, pp. 2903–2910, 2005.
[101]
H. Dote, D. Cerna, W. E. Burgan et al., “Enhancement of in vitro and in vivo tumor cell radiosensitivity by the DNA methylation inhibitor zebularine,” Clinical Cancer Research, vol. 11, no. 12, pp. 4571–4579, 2005.
[102]
S. Honda, M. Haruta, W. Sugawara et al., “The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients,” International Journal of Cancer, vol. 123, no. 5, pp. 1117–1125, 2008.
[103]
M. J. Beyrouthy, K. M. Garner, M. P. Hever et al., “High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors,” Cancer Research, vol. 69, no. 24, pp. 9360–9366, 2009.
[104]
Q.-Z. Zhao and K.-F. Dou, “Methylation of Ras association domain family protein 1, isoform a correlated with proliferation and drug resistance in hepatocellular carcinoma cell line SMMC-7721,” Journal of Gastroenterology and Hepatology, vol. 22, no. 5, pp. 683–689, 2007.
[105]
G. Garcia-Manero, H. M. Kantarjian, B. Sanchez-Gonzalez et al., “Phase 1/2 study of the combination of 5-aza- -deoxycytidine with valproic acid in patients with leukemia,” Blood, vol. 108, no. 10, pp. 3271–3279, 2006.
[106]
B. Rüter, P. W. Wijermans, and M. Lübbert, “Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2′-deoxycytidine retreatment in high-risk myelodysplasia patients,” Cancer, vol. 106, no. 8, pp. 1744–1750, 2006.
[107]
J. Levesley, et al., “RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines,” Neuro-Oncology, vol. 13, no. 12, pp. 1265–1276, 2011.
[108]
Y. J. Zhang, H. Ahsan, Y. Chen et al., “High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma,” Molecular Carcinogenesis, vol. 35, no. 2, pp. 85–92, 2002.
[109]
K. Akino, M. Toyota, H. Suzuki et al., “The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer,” Gastroenterology, vol. 129, no. 1, pp. 156–169, 2005.
[110]
M. Endoh, G. Tamura, T. Honda et al., “RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer,” British Journal of Cancer, vol. 93, no. 12, pp. 1395–1399, 2005.
[111]
L. B. Hesson, R. Wilson, D. Morton et al., “CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations,” Oncogene, vol. 24, no. 24, pp. 3987–3994, 2005.
[112]
H. W. Park, C. K. Hio, I. J. Kim et al., “Correlation between hypermethylation of the RASSF2A promoter and K-ras/BRAF mutations in microsatellite-stable colorectal cancers,” International Journal of Cancer, vol. 120, no. 1, pp. 7–12, 2007.
[113]
M. D. Vos, C. A. Ellis, C. Elam, A. S. ülkü, B. J. Taylor, and G. J. Clark, “RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor,” Journal of Biological Chemistry, vol. 278, no. 30, pp. 28045–28051, 2003.
[114]
Z. Zhang, D. Sun, N. V. Do, A. Tang, L. Hu, and G. Huang, “Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma,” International Journal of Cancer, vol. 120, no. 1, pp. 32–38, 2007.
[115]
E. T. Sakamoto-Hojo, S. S. Mello, E. Pereira et al., “Gene expression profiles in human cells submitted to genotoxic stress,” Mutation Research - Reviews in Mutation Research, vol. 544, no. 2-3, pp. 403–413, 2003.
[116]
W. N. Cooper, L. B. Hesson, D. Matallanas et al., “RASSF2 associates with and stabilizes the proapoptotic kinase MST2,” Oncogene, vol. 28, no. 33, pp. 2988–2998, 2009.
[117]
N. P. C. Allen, H. Donninger, M. D. Vos et al., “RASSF6 is a novel member of the RASSF family of tumor suppressors,” Oncogene, vol. 26, no. 42, pp. 6203–6211, 2007.
[118]
M. Ikeda, S. Hirabayashi, N. Fujiwara et al., “Ras-association domain family protein 6 induces apoptosis via both caspase-dependent and caspase-independent pathways,” Experimental Cell Research, vol. 313, no. 7, pp. 1484–1495, 2007.
[119]
M. Ikeda, A. Kawata, M. Nishikawa et al., “Hippo pathway-dependent and-independent roles of RASSF6,” Science Signaling, vol. 2, no. 90, article ra59, 2009.
[120]
S. Ortiz-Vega, A. Khokhlatchev, M. Nedwidek et al., “The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1,” Oncogene, vol. 21, no. 9, pp. 1381–1390, 2002.
[121]
J. N. Weitzel, A. Kasperczyk, C. Mohan, and T. G. Krontiris, “The HRAS1 gene cluster: two upstream regions recognizing transcripts and a third encoding a gene with a leucine zipper domain,” Genomics, vol. 14, no. 2, pp. 309–319, 1992.
[122]
T. G. Krontiris, B. Devlin, D. D. Karp, N. J. Robert, and N. Risch, “An association between the risk of cancer and mutations in the HRAS1 minisatellite locus,” New England Journal of Medicine, vol. 329, no. 8, pp. 517–523, 1993.
[123]
T. G. Krontiris, N. A. DiMartino, M. Colb, and D. R. Parkinson, “Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients,” Nature, vol. 313, no. 6001, pp. 369–374, 1985.
[124]
H. Friess, J. Ding, J. Kleeff et al., “Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer,” Cellular and Molecular Life Sciences, vol. 60, no. 6, pp. 1180–1199, 2003.
[125]
C. D. Logsdon, D. M. Simeone, C. Binkley et al., “Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer,” Cancer Research, vol. 63, no. 10, pp. 2649–2657, 2003.
[126]
A. W. Lowe, M. Olsen, Y. Hao et al., “Gene expression patterns in pancreatic tumors, cells and tissues,” PLoS One, vol. 2, no. 3, article e323, 2007.
[127]
G. L. Mutter, J. P.A. Baak, J. T. Fitzgerald et al., “Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation,” Gynecologic Oncology, vol. 83, no. 2, pp. 177–185, 2001.
[128]
D. S. P. Tan, M. B. K. Lambros, S. Rayter et al., “PPM1D is a potential therapeutic target in ovarian clear cell carcinomas,” Clinical Cancer Research, vol. 15, no. 7, pp. 2269–2280, 2009.
[129]
S. Takahashi, A. Ebihara, H. Kajiho, K. Kontani, H. Nishina, and T. Katada, “RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7,” Cell Death and Differentiation, vol. 18, no. 4, pp. 645–655, 2011.
