Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Genetic determinants at the interface of cancer and neurodegenerative disease

Oncogene volume 29, pages 3453–3464 (2010)Cite this article

Subjects

Abstract

It has been hypothesized that oncogenesis and neurodegeneration may share common mechanistic foundations. Recent evidence now reveals a number of genes in which alteration leads to either carcinogenesis or neurodegeneration, depending on cellular context. Pathways that have emerged as having critical roles in both cancer and neurodegenerative disease include those involving genes such as PARK2, ATM, PTEN, PTPRD, and mTOR. A number of mechanisms have been implicated, and commonly affected cellular processes include cell cycle regulation, DNA repair, and response to oxidative stress. For example, we have recently shown that the E3 ubiquitin ligase PARK2 is mutated or deleted in many different human malignancies and helps drive loss on chromosome 6q25.2–27, a genomic region frequently deleted in cancers. Mutation in PARK2 is also the most common cause of juvenile Parkinson's disease. Mutations in PARK2 result in an upregulation of its substrate cyclin E, resulting in dysregulated entry into the cell cycle. In neurons, this process results in cell death, but in cycling cells, the result is a growth advantage. Thus, depending on whether the cell affected is a dividing cell or a post-mitotic neuron, responses to these alterations may differ, ultimately leading to varying disease phenotypes. Here, we review the substantial data implicating specific genes in both cancer and neurodegenerative disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Abbas N, Lucking CB, Ricard S, Durr A, Bonifati V, De Michele G et al. (1999). A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's disease genetics study group and the European consortium on genetic susceptibility in parkinson's disease. Hum Mol Genet 8: 567–574.

    CAS  Google Scholar 

  • Ackman JB, Ramos RL, Sarkisian MR, Loturco JJ . (2007). Citron kinase is required for postnatal neurogenesis in the hippocampus. Dev Neurosci 29: 113–123.

    CAS  Google Scholar 

  • Agirre X, Roman-Gomez J, Vazquez I, Jimenez-Velasco A, Garate L, Montiel-Duarte C et al. (2006). Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. Int J Cancer 118: 1945–1953.

    CAS  Google Scholar 

  • Alderton GK, Joenje H, Varon R, Borglum AD, Jeggo PA, O'Driscoll M . (2004). Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. Hum Mol Genet 13: 3127–3138.

    CAS  Google Scholar 

  • Anandatheerthavarada HK, Devi L . (2007). Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease. Neuroscientist 13: 626–638.

    CAS  Google Scholar 

  • Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P et al. (2001). The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276: 35243–35246.

    CAS  Google Scholar 

  • Arvidsson Y, Andersson E, Bergstrom A, Andersson MK, Altiparmak G, Illerskog AC et al. (2008). Amyloid precursor-like protein 1 is differentially upregulated in neuroendocrine tumours of the gastrointestinal tract. Endocr Relat Cancer 15: 569–581.

    CAS  Google Scholar 

  • Auclair Y, Rouget R, Affar el B, Drobetsky EA . (2008). ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells. Proc Natl Acad Sci USA 105: 17896–17901.

    CAS  Google Scholar 

  • Baldus CD, Liyanarachchi S, Mrozek K, Auer H, Tanner SM, Guimond M et al. (2004). Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA 101: 3915–3920.

    CAS  Google Scholar 

  • Ball LG, Xiao W . (2005). Molecular basis of ataxia telangiectasia and related diseases. Acta Pharmacol Sin 26: 897–907.

    CAS  Google Scholar 

  • Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L et al. (1998). Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281: 1674–1677.

    CAS  Google Scholar 

  • Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A et al. (2001). ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 411: 969–974.

    CAS  Google Scholar 

  • Beal MF . (2005). Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58: 495–505.

    CAS  Google Scholar 

  • Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN et al. (2006). Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15: 433–442.

    CAS  Google Scholar 

  • Bixby JL . (2000). Receptor tyrosine phosphatases in axon growth and guidance. Neuroreport 11: R5–10.

    CAS  Google Scholar 

  • Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E et al. (2003). Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299: 256–259.

    CAS  Google Scholar 

  • Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, Bohl J . (1996). Pattern of brain destruction in Parkinson's and Alzheimer's diseases. J Neural Transm 103: 455–490.

    CAS  Google Scholar 

  • Brion JP, Couck AM . (1995). Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5. Am J Pathol 147: 1465–1476.

    CAS  Google Scholar 

  • Burtelow MA, Roos-Mattjus PM, Rauen M, Babendure JR, Karnitz LM . (2001). Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9–1–1) DNA damage responsive checkpoint complex. J Biol Chem 276: 25903–25909.

    CAS  Google Scholar 

  • Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG et al. (1997). Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 57: 4997–5000.

    CAS  Google Scholar 

  • Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K et al. (1998). Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281: 1677–1679.

    CAS  Google Scholar 

  • Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H et al. (2003). Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci USA 100: 5956–5961.

    CAS  Google Scholar 

  • Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, Cope L et al. (2008). Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5: e114.

    Google Scholar 

  • Chan TA, Heguy A . (2009). The protein tyrosine phosphatase receptor D, a broadly inactivated tumor suppressor regulating STAT function. Cell Cycle 8: 3063–3064.

    CAS  Google Scholar 

  • Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH et al. (2003). Interaction of Akt-phosphorylated ataxin-1 with 14–3–3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113: 457–468.

    CAS  Google Scholar 

  • Cheng G, Yu Z, Zhou D, Mattson MP . (2002). Phosphatidylinositol-3-kinase-Akt kinase and p42/p44 mitogen-activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein. Exp Neurol 175: 407–414.

    CAS  Google Scholar 

  • Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M et al. (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303: 1010–1014.

    CAS  Google Scholar 

  • Chun HH, Gatti RA . (2004). Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst) 3: 1187–1196.

    CAS  Google Scholar 

  • Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL et al. (1998). Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J 17: 159–169.

    CAS  Google Scholar 

  • Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG et al. (2003). Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61: 304–309.

    CAS  Google Scholar 

  • Corti O, Hampe C, Darios F, Ibanez P, Ruberg M, Brice A . (2005). Parkinson's disease: from causes to mechanisms. C R Biol 328: 131–142.

    CAS  Google Scholar 

  • Darios F, Corti O, Lucking CB, Hampe C, Muriel MP, Abbas N et al. (2003). Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 12: 517–526.

    CAS  Google Scholar 

  • Delgado-Esteban M, Martin-Zanca D, Andres-Martin L, Almeida A, Bolanos JP . (2007). Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway. J Neurochem 102: 194–205.

    CAS  Google Scholar 

  • den Hertog J, Blanchetot C, Buist A, Overvoorde J, van der Sar A, Tertoolen LG . (1999). Receptor protein-tyrosine phosphatase signalling in development. Int J Dev Biol 43: 723–733.

    CAS  Google Scholar 

  • Deshpande A, Sicinski P, Hinds PW . (2005). Cyclins and cdks in development and cancer: a perspective. Oncogene 24: 2909–2915.

    CAS  Google Scholar 

  • Donnellan R, Chetty R . (1999). Cyclin E in human cancers. FASEB J 13: 773–780.

    CAS  Google Scholar 

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.

    Article  CAS  Google Scholar 

  • Eng C . (2000). Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 37: 828–830.

    CAS  Google Scholar 

  • Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J . (2001). The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410: 842–847.

    CAS  Google Scholar 

  • Farina L, Uggetti C, Ottolini A, Martelli A, Bergamaschi R, Sibilla L et al. (1994). Ataxia-telangiectasia: MR and CT findings. J Comput Assist Tomogr 18: 724–727.

    CAS  Google Scholar 

  • Fearnley JM, Lees AJ . (1991). Ageing and Parkinson′s disease: substantia nigra regional selectivity. Brain 114: 2283–2301.

    Google Scholar 

  • Fegan C, Robinson H, Thompson P, Whittaker JA, White D . (1995). Karyotypic evolution in CLL: identification of a new sub-group of patients with deletions of 11q and advanced or progressive disease. Leukemia 9: 2003–2008.

    CAS  Google Scholar 

  • Feng Z, Zhang H, Levine AJ, Jin S . (2005). The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102: 8204–8209.

    CAS  Google Scholar 

  • Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M et al. (2009). Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 325: 1261–1265.

    CAS  Google Scholar 

  • Gakhar-Koppole N, Hundeshagen P, Mandl C, Weyer SW, Allinquant B, Muller U et al. (2008). Activity requires soluble amyloid precursor protein alpha to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway. Eur J Neurosci 28: 871–882.

    Google Scholar 

  • Gatti RA, Tward A, Concannon P . (1999). Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 68: 419–423.

    CAS  Google Scholar 

  • Gegg ME, Cooper JM, Schapira AH, Taanman JW . (2009). Silencing of PINK1 expression affects mitochondrial DNA and oxidative phosphorylation in dopaminergic cells. PLoS One 4: e4756.

    Google Scholar 

  • Giardina SF, Beart PM . (2002). Kainate receptor-mediated apoptosis in primary cultures of cerebellar granule cells is attenuated by mitogen-activated protein and cyclin-dependent kinase inhibitors. Br J Pharmacol 135: 1733–1742.

    CAS  Google Scholar 

  • Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken HH, Becker D et al. (2009). Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One 4: e5777.

    Google Scholar 

  • Gozuacik D, Kimchi A . (2004). Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23: 2891–2906.

    CAS  Google Scholar 

  • Gozuacik D, Kimchi A . (2007). Autophagy and cell death. Curr Top Dev Biol 78: 217–245.

    CAS  Google Scholar 

  • Griffin RJ, Moloney A, Kelliher M, Johnston JA, Ravid R, Dockery P et al. (2005). Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J Neurochem 93: 105–117.

    CAS  Google Scholar 

  • Gronbaek K, Zeuthen J, Guldberg P, Ralfkiaer E, Hou-Jensen K . (1998). Alterations of the MMAC1/PTEN gene in lymphoid malignancies. Blood 91: 4388–4390.

    CAS  Google Scholar 

  • Gumy-Pause F, Wacker P, Maillet P, Betts DR, Sappino AP . (2006). ATM variants and predisposition to childhood T-lineage acute lymphoblastic leukaemia. Leukemia 20: 526–527, author reply 527.

    CAS  Google Scholar 

  • Hampe C, Ardila-Osorio H, Fournier M, Brice A, Corti O . (2006). Biochemical analysis of Parkinson′s disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum Mol Genet 15: 2059–2075.

    CAS  Google Scholar 

  • Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A . (2003). Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res 63: 7032–7037.

    CAS  Google Scholar 

  • Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC . (1999). Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98: 859–869.

    CAS  Google Scholar 

  • Husseman JW, Nochlin D, Vincent I . (2000). Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging 21: 815–828.

    CAS  Google Scholar 

  • Huynh DP, Nguyen DT, Pulst-Korenberg JB, Brice A, Pulst SM . (2007). Parkin is an E3 ubiquitin-ligase for normal and mutant ataxin-2 and prevents ataxin-2-induced cell death. Exp Neurol 203: 531–541.

    CAS  Google Scholar 

  • Imai Y, Soda M, Takahashi R . (2000). Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275: 35661–35664.

    CAS  Google Scholar 

  • Inglis KJ, Chereau D, Brigham EF, Chiou SS, Schobel S, Frigon NL et al. (2009). Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem 284: 2598–2602.

    CAS  Google Scholar 

  • Inskip HM, Kinlen LJ, Taylor AM, Woods CG, Arlett CF . (1999). Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. Br J Cancer 79: 1304–1307.

    CAS  Google Scholar 

  • Inzelberg R, Jankovic J . (2007). Are Parkinson disease patients protected from some but not all cancers? Neurology 69: 1542–1550.

    Google Scholar 

  • Ishiguro M, Ohsawa I, Takamura C, Morimoto T, Kohsaka S . (1998). Secreted form of beta-amyloid precursor protein activates protein kinase C and phospholipase Cgamma1 in cultured embryonic rat neocortical cells. Brain Res Mol Brain Res 53: 24–32.

    CAS  Google Scholar 

  • Johnson KG, Van Vactor D . (2003). Receptor protein tyrosine phosphatases in nervous system development. Physiol Rev 83: 1–24.

    CAS  Google Scholar 

  • Kerr F, Rickle A, Nayeem N, Brandner S, Cowburn RF, Lovestone S . (2006). PTEN, a negative regulator of PI3 kinase signalling, alters tau phosphorylation in cells by mechanisms independent of GSK-3. FEBS Lett 580: 3121–3128.

    CAS  Google Scholar 

  • Kim RH, Mak TW . (2006). Tumours and tremors: how PTEN regulation underlies both. Br J Cancer 94: 620–624.

    CAS  Google Scholar 

  • Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S et al. (2005). Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102: 5215–5220.

    CAS  Google Scholar 

  • Kim SK, Su LK, Oh Y, Kemp BL, Hong WK, Mao L . (1998). Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines. Oncogene 16: 89–93.

    CAS  Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392: 605–608.

    CAS  Google Scholar 

  • Klionsky DJ, Ohsumi Y . (1999). Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 15: 1–32.

    CAS  Google Scholar 

  • Ko SY, Lin SC, Chang KW, Wong YK, Liu CJ, Chi CW et al. (2004). Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer 111: 727–732.

    CAS  Google Scholar 

  • Kohno T, Takahashi M, Manda R, Yokota J . (1998). Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer 22: 152–156.

    CAS  Google Scholar 

  • Krause K, Karger S, Sheu SY, Aigner T, Kursawe R, Gimm O et al. (2008). Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis. J Endocrinol 198: 291–299.

    CAS  Google Scholar 

  • Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ et al. (2004). Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41: 549–561.

    CAS  Google Scholar 

  • Lavin MF, Kozlov S . (2007). ATM activation and DNA damage response. Cell Cycle 6: 931–942.

    CAS  Google Scholar 

  • Lee HC, Kim M, Wands JR . (2006). Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci 11: 1901–1915.

    CAS  Google Scholar 

  • Lee Y, McKinnon PJ . (2007). Responding to DNA double strand breaks in the nervous system. Neuroscience 145: 1365–1374.

    CAS  Google Scholar 

  • Levine B, Yuan J . (2005). Autophagy in cell death: an innocent convict? J Clin Invest 115: 2679–2688.

    CAS  Google Scholar 

  • Lewis KA, Mullany S, Thomas B, Chien J, Loewen R, Shridhar V et al. (2005). Heterozygous ATR mutations in mismatch repair-deficient cancer cells have functional significance. Cancer Res 65: 7091–7095.

    CAS  Google Scholar 

  • Liang Y, Lin SY, Brunicardi FC, Goss J, Li K . (2009). DNA damage response pathways in tumor suppression and cancer treatment. World J Surg 33: 661–666.

    Google Scholar 

  • Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A . (2001). Purification and characterization of human DNA damage checkpoint Rad complexes. Proc Natl Acad Sci USA 98: 11236–11241.

    CAS  Google Scholar 

  • Lovestone S, Reynolds CH . (1997). The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 78: 309–324.

    CAS  Google Scholar 

  • Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T et al. (2000). Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 342: 1560–1567.

    CAS  Google Scholar 

  • Mao JH, Perez-Losada J, Wu D, Delrosario R, Tsunematsu R, Nakayama KI et al. (2004). Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 432: 775–779.

    CAS  Google Scholar 

  • Marino S, Krimpenfort P, Leung C, van der Korput HA, Trapman J, Camenisch I et al. (2002). PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development 129: 3513–3522.

    CAS  Google Scholar 

  • Matrone C, Di Luzio A, Meli G, D′Aguanno S, Severini C, Ciotti MT et al. (2008). Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells. J Alzheimers Dis 13: 81–96.

    CAS  Google Scholar 

  • Matsumoto T, Wang PY, Ma W, Sung HJ, Matoba S, Hwang PM . (2009). Polo-like kinases mediate cell survival in mitochondrial dysfunction. Proc Natl Acad Sci USA 106: 14542–14546.

    CAS  Google Scholar 

  • Mavrou A, Tsangaris GT, Roma E, Kolialexi A . (2008). The ATM gene and ataxia telangiectasia. Anticancer Res 28: 401–405.

    CAS  Google Scholar 

  • Mazieres J, He B, You L, Xu Z, Jablons DM . (2005). Wnt signaling in lung cancer. Cancer Lett 222: 1–10.

    CAS  Google Scholar 

  • Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG . (2005). ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 4: 1166–1170.

    CAS  Google Scholar 

  • Milne RL . (2009). Variants in the ATM gene and breast cancer susceptibility. Genome Med 1: 12.

    Google Scholar 

  • Moller H, Mellemkjaer L, McLaughlin JK, Olsen JH . (1995). Occurrence of different cancers in patients with Parkinson′s disease. BMJ 310: 1500–1501.

    CAS  Google Scholar 

  • Moore DJ, West AB, Dikeman DA, Dawson VL, Dawson TM . (2008). Parkin mediates the degradation-independent ubiquitination of Hsp70. J Neurochem 105: 1806–1819.

    CAS  Google Scholar 

  • Morrell D, Cromartie E, Swift M . (1986). Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 77: 89–92.

    CAS  Google Scholar 

  • Nguyen MD, Mushynski WE, Julien JP . (2002). Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 9: 1294–1306.

    CAS  Google Scholar 

  • Nishimura I, Takazaki R, Kuwako K, Enokido Y, Yoshikawa K . (2003). Upregulation and antiapoptotic role of endogenous Alzheimer amyloid precursor protein in dorsal root ganglion neurons. Exp Cell Res 286: 241–251.

    CAS  Google Scholar 

  • Nouspikel T, Hanawalt PC . (2003). When parsimony backfires: neglecting DNA repair may doom neurons in Alzheimer's disease. Bioessays 25: 168–173.

    CAS  Google Scholar 

  • Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM . (2004). Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 144: 505–511.

    Google Scholar 

  • Nunan J, Small DH . (2000). Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 483: 6–10.

    CAS  Google Scholar 

  • O′Driscoll M, Jackson AP, Jeggo PA . (2006). Microcephalin: a causal link between impaired damage response signalling and microcephaly. Cell Cycle 5: 2339–2344.

    Google Scholar 

  • Olanow CW, Tatton WG . (1999). Etiology and pathogenesis of Parkinson's disease. Annu Rev Neurosci 22: 123–144.

    CAS  Google Scholar 

  • Olsen JH, Friis S, Frederiksen K, McLaughlin JK, Mellemkjaer L, Moller H . (2005). Atypical cancer pattern in patients with Parkinson's disease. Br J Cancer 92: 201–205.

    CAS  Google Scholar 

  • Orii KE, Lee Y, Kondo N, McKinnon PJ . (2006). Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. Proc Natl Acad Sci USA 103: 10017–10022.

    CAS  Google Scholar 

  • Park DS, Levine B, Ferrari G, Greene LA . (1997). Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J Neurosci 17: 8975–8983.

    CAS  Google Scholar 

  • Park DS, Morris EJ, Stefanis L, Troy CM, Shelanski ML, Geller HM et al. (1998). Multiple pathways of neuronal death induced by DNA-damaging agents, NGF deprivation, and oxidative stress. J Neurosci 18: 830–840.

    CAS  Google Scholar 

  • Parker Jr WD . (1991). Cytochrome oxidase deficiency in Alzheimer's disease. Ann N Y Acad Sci 640: 59–64.

    Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812.

    CAS  Google Scholar 

  • Pei JJ, Khatoon S, An WL, Nordlinder M, Tanaka T, Braak H et al. (2003). Role of protein kinase B in Alzheimer's neurofibrillary pathology. Acta Neuropathol 105: 381–392.

    CAS  Google Scholar 

  • Petrucelli L, O′Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L et al. (2002). Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36: 1007–1019.

    CAS  Google Scholar 

  • Pridgeon JW, Olzmann JA, Chin LS, Li L . (2007). PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5: e172.

    Google Scholar 

  • Prokopcova J, Kleibl Z, Banwell CM, Pohlreich P . (2007). The role of ATM in breast cancer development. Breast Cancer Res Treat 104: 121–128.

    CAS  Google Scholar 

  • Querfurth HW, LaFerla FM . (2010). Alzheimer's disease. N Engl J Med 362: 329–344.

    CAS  Google Scholar 

  • Rauen M, Burtelow MA, Dufault VM, Karnitz LM . (2000). The human checkpoint protein hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9. J Biol Chem 275: 29767–29771.

    CAS  Google Scholar 

  • Ravikumar B, Rubinsztein DC . (2006). Role of autophagy in the clearance of mutant huntingtin: a step towards therapy? Mol Aspects Med 27: 520–527.

    CAS  Google Scholar 

  • Ravikumar B, Sarkar S, Rubinsztein DC . (2008). Clearance of mutant aggregate-prone proteins by autophagy. Methods Mol Biol 445: 195–211.

    CAS  Google Scholar 

  • Rawal N, Corti O, Sacchetti P, Ardilla-Osorio H, Sehat B, Brice A et al. (2009). Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling. Biochem Biophys Res Commun 388: 473–478.

    CAS  Google Scholar 

  • Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M et al. (2006). ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38: 873–875.

    CAS  Google Scholar 

  • Rickle A, Bogdanovic N, Volkman I, Winblad B, Ravid R, Cowburn RF . (2004). Akt activity in Alzheimer's disease and other neurodegenerative disorders. Neuroreport 15: 955–959.

    CAS  Google Scholar 

  • Rickle A, Bogdanovic N, Volkmann I, Zhou X, Pei JJ, Winblad B et al. (2006). PTEN levels in Alzheimer's disease medial temporal cortex. Neurochem Int 48: 114–123.

    CAS  Google Scholar 

  • Rideout HJ, Wang Q, Park DS, Stefanis L . (2003). Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition. J Neurosci 23: 1237–1245.

    CAS  Google Scholar 

  • Roos-Mattjus P, Vroman BT, Burtelow MA, Rauen M, Eapen AK, Karnitz LM . (2002). Genotoxin-induced Rad9-Hus1-Rad1 (9–1–1) chromatin association is an early checkpoint signaling event. J Biol Chem 277: 43809–43812.

    CAS  Google Scholar 

  • Sansal I, Sellers WR . (2004). The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22: 2954–2963.

    CAS  Google Scholar 

  • Schmitz A, Tikkanen R, Kirfel G, Herzog V . (2002). The biological role of the Alzheimer amyloid precursor protein in epithelial cells. Histochem Cell Biol 117: 171–180.

    CAS  Google Scholar 

  • Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A . (2004). DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2: e362.

    Google Scholar 

  • Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S et al. (2000). Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25: 302–305.

    CAS  Google Scholar 

  • Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R et al. (2001). Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293: 263–269.

    CAS  Google Scholar 

  • Shineman DW, Dain AS, Kim ML, Lee VM . (2009). Constitutively active Akt inhibits trafficking of amyloid precursor protein and amyloid precursor protein metabolites through feedback inhibition of phosphoinositide 3-kinase. Biochemistry 48: 3787–3794.

    CAS  Google Scholar 

  • Solomon DA, Kim JS, Cronin JC, Sibenaller Z, Ryken T, Rosenberg SA et al. (2008). Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma. Cancer Res 68: 10300–10306.

    CAS  Google Scholar 

  • Sriram SR, Li X, Ko HS, Chung KK, Wong E, Lim KL et al. (2005). Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin. Hum Mol Genet 14: 2571–2586.

    CAS  Google Scholar 

  • Staropoli JF . (2008). Tumorigenesis and neurodegeneration: two sides of the same coin? Bioessays 30: 719–727.

    CAS  Google Scholar 

  • Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A . (2003). Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37: 735–749.

    CAS  Google Scholar 

  • Stein TD, Johnson JA . (2002). Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J Neurosci 22: 7380–7388.

    CAS  Google Scholar 

  • Stepanek L, Stoker AW, Stoeckli E, Bixby JL . (2005). Receptor tyrosine phosphatases guide vertebrate motor axons during development. J Neurosci 25: 3813–3823.

    CAS  Google Scholar 

  • Subba Rao K . (2007). Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol 3: 162–172.

    Google Scholar 

  • Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT . (1986). The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39: 573–583.

    CAS  Google Scholar 

  • Tabira T, Chui DH, Kuroda S . (2002). Significance of intracellular Abeta42 accumulation in Alzheimer's disease. Front Biosci 7: a44–a49.

    CAS  Google Scholar 

  • Tanaka K, Suzuki T, Chiba T, Shimura H, Hattori N, Mizuno Y . (2001). Parkin is linked to the ubiquitin pathway. J Mol Med 79: 482–494.

    CAS  Google Scholar 

  • Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST et al. (2002). Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109: 459–472.

    CAS  Google Scholar 

  • TCGA (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways (Cancer Genome Atlas Network). Nature 455: 1061–1068.

    Google Scholar 

  • Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A et al. (2005). Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97: 813–822.

    CAS  Google Scholar 

  • Toma MI, Grosser M, Herr A, Aust DE, Meye A, Hoefling C et al. (2008). Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array. Neoplasia 10: 634–642.

    CAS  Google Scholar 

  • Tsuchihara K, Fujii S, Esumi H . (2009). Autophagy and cancer: dynamism of the metabolism of tumor cells and tissues. Cancer Lett 278: 130–138.

    CAS  Google Scholar 

  • Uetani N, Chagnon MJ, Kennedy TE, Iwakura Y, Tremblay ML . (2006). Mammalian motoneuron axon targeting requires receptor protein tyrosine phosphatases sigma and delta. J Neurosci 26: 5872–5880.

    CAS  Google Scholar 

  • Uetani N, Kato K, Ogura H, Mizuno K, Kawano K, Mikoshiba K et al. (2000). Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice. EMBO J 19: 2775–2785.

    CAS  Google Scholar 

  • Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S et al. (2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304: 1158–1160.

    CAS  Google Scholar 

  • Veeriah S, Brennan C, Meng S, Singh B, Fagin JA, Solit DB et al. (2009a). The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. Proc Natl Acad Sci USA 106: 9435–9440.

    CAS  Google Scholar 

  • Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I et al. (2009b). Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 42: 77–82.

    Google Scholar 

  • Verdaguer E, Garcia-Jorda E, Canudas AM, Dominguez E, Jimenez A, Pubill D et al. (2002). Kainic acid-induced apoptosis in cerebellar granule neurons: an attempt at cell cycle re-entry. Neuroreport 13: 413–416.

    CAS  Google Scholar 

  • Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J et al. (2009). PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 107: 378–383.

    Google Scholar 

  • Wang T, Lao U, Edgar BA . (2009). TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 186: 703–711.

    CAS  Google Scholar 

  • Wei W, Wang X, Kusiak JW . (2002). Signaling events in amyloid beta-peptide-induced neuronal death and insulin-like growth factor I protection. J Biol Chem 277: 17649–17656.

    CAS  Google Scholar 

  • Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R et al. (2007). Characterizing the cancer genome in lung adenocarcinoma. Nature 450: 893–898.

    CAS  Google Scholar 

  • Wong KK, Engelman JA, Cantley LC . (2009). Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev PMID: 20006486.

  • Xavier AC, Ge Y, Taub JW . (2009). Down syndrome and malignancies: a unique clinical relationship: a paper from the 2008 william beaumont hospital symposium on molecular pathology. J Mol Diagn 11: 371–380.

    CAS  Google Scholar 

  • Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C et al. (2009). Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest 119: 650–660.

    CAS  Google Scholar 

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . (1993). p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704.

    CAS  Google Scholar 

  • Yang H, Zhou HY, Li B, Niu GZ, Chen SD . (2007). Downregulation of parkin damages antioxidant defenses and enhances proteasome inhibition-induced toxicity in PC12 cells. J Neuroimmune Pharmacol 2: 276–283.

    Google Scholar 

  • Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L . (2003). PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100: 1931–1936.

    CAS  Google Scholar 

  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM . (2000). Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97: 13354–13359.

    CAS  Google Scholar 

  • Zhu Y, Hoell P, Ahlemeyer B, Krieglstein J . (2006). PTEN: a crucial mediator of mitochondria-dependent apoptosis. Apoptosis 11: 197–207.

    CAS  Google Scholar 

  • Zighelboim I, Schmidt AP, Gao F, Thaker PH, Powell MA, Rader JS et al. (2009). ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. J Clin Oncol 27: 3091–3096.

    CAS  Google Scholar 

Download references

Acknowledgements

We thank the Head and Neck Service, Department of Surgery at Memorial Sloan-Kettering Cancer Center for support (LGTM). LGTM is supported by National Cancer Institute T32 Grant CA009685. TAC is supported by the Doris Duke Charitable Foundation, the Society of Memorial Sloan-Kettering Foundation, the Flight Attendant Medical Research Institute, the Louis Gerstner Foundation, the Memorial Sloan-Kettering Brain Tumor Center, and the STARR Cancer Consortium.

Author information

Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    L G T Morris, S Veeriah & T A Chan

  2. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    L G T Morris

  3. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    T A Chan

  4. Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    T A Chan

Authors
  1. L G T Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Veeriah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T A Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T A Chan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morris, L., Veeriah, S. & Chan, T. Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene 29, 3453–3464 (2010). https://doi.org/10.1038/onc.2010.127

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.127

Keywords

This article is cited by

Search

Advanced search

Quick links