Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.

Vault poly(ADP-ribose) polymerase (VPARP) and telomerase-associated protein 1 (TEP1) are components of the vault ribonucleoprotein complex. Vaults have been implicated in multidrug resistance of human tumors and are thought to be involved in macromolecular assembly and/or transport. Previous studies showed that VPARP-deficient mice were viable, fertile, and did not display any vault-related or telomerase-related phenotype, whereas disruption of telomerase-associated protein 1 in mice led to reduced stability of the vault RNA and affected its stable association with vaults, although there were no telomerase-related changes. In this study, we evaluated the susceptibility of Vparp-/- and Tep1-/- mice to dimethylhydrazine-induced colon tumorigenesis and urethane-induced lung tumorigenesis. Mice received i.p. injections of either 1 g/kg body weight of urethane twice a week for 2 weeks or 20 mg/kg body weight of dimethylhydrazine once a week for 10 weeks and were analyzed after 10 and 60 weeks, respectively. The colon tumor incidence and multiplicity were significantly higher and colon tumor latency was significantly shorter in Vparp-/- mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1-/- mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparp-/- and Tep1-/- mice but were not significant. The increase in carcinogen-induced tumors in VPARP-deficient mice is the only phenotype observed to date, and suggests a possible role for VPARP, directly or indirectly, in chemically induced neoplasia.

[1]  T. Ried,et al.  Chromosomal aberrations in PARP(-/-) mice: genome stabilization in immortalized cells by reintroduction of poly(ADP-ribose) polymerase cDNA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Chin,et al.  Telomere dysfunction alters the chemotherapeutic profile of transformed cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Finnon,et al.  Short Telomeres Result in Organismal Hypersensitivity to Ionizing Radiation in Mammals , 2000, The Journal of experimental medicine.

[4]  E. Gilson,et al.  Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2 , 2004, Molecular and Cellular Biology.

[5]  D. Chugani,et al.  Unlocking vaults: organelles in search of a function. , 1991, Trends in cell biology.

[6]  A. Matsuura,et al.  TLP1: A Gene Encoding a Protein Component of Mammalian Telomerase Is a Novel Member of WD Repeats Family , 1997, Cell.

[7]  L. Rome,et al.  Recombinant Major Vault Protein Is Targeted to Neuritic Tips of PC12 Cells , 1999, The Journal of cell biology.

[8]  C. Greider,et al.  Telomerase activation: one step on the road to cancer? , 1999 .

[9]  H. Autrup,et al.  Methylated DNA adducts in the large intestine of ICR/Ha and C57BL/Ha mice given 1,2-dimethylhydrazine. , 1983, Journal of the National Cancer Institute.

[10]  M. Prakash Hande,et al.  Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability , 1999, Nature Genetics.

[11]  M. Blasco,et al.  Telomere dysfunction results in enhanced organismal sensitivity to the alkylating agent N-methyl-N-nitrosourea. , 2003, Cancer research.

[12]  K. Suprenant,et al.  Characterization of the sea urchin major vault protein: a possible role for vault ribonucleoprotein particles in nucleocytoplasmic transport. , 1997, Developmental biology.

[13]  I. Roninson,et al.  Activation of the LRP (lung resistance-related protein) gene by short-term exposure of human leukemia cells to phorbol ester and cytarabine. , 1998, Oncology research.

[14]  G. de Murcia,et al.  The PARP superfamily , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[15]  T. Sugimura,et al.  Increased susceptibility of poly(ADP-ribose) polymerase-1 knockout mice to nitrosamine carcinogenicity. , 2001, Carcinogenesis.

[16]  V. Kickhoefer,et al.  The Mr 193,000 vault protein is up-regulated in multidrug-resistant cancer cell lines. , 2000, Cancer research.

[17]  M. Bass,et al.  Human telomerase contains evolutionarily conserved catalytic and structural subunits. , 1997, Genes & development.

[18]  M. Santibanez-Koref,et al.  O6-alkylguanine-DNA alkyltransferase: role in carcinogenesis and chemotherapy. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[19]  A. Smogorzewska,et al.  Regulation of telomerase by telomeric proteins. , 2004, Annual review of biochemistry.

[20]  V. Kickhoefer,et al.  Up‐regulation of vaults may be necessary but not sufficient for multidrug resistance , 2001, International journal of cancer.

[21]  G. Steele,et al.  Cancer: Principles and Practice of Oncology , 1983 .

[22]  Sandy Chang,et al.  Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice , 1999, Cell.

[23]  A. Mittelman,et al.  Brief Communication: Differential Susceptibility of Four Mouse Strains to Induction of Multiple Large-Bowel Neoplasms by 1,2-Dimethylhydrazine , 1974 .

[24]  D. Corey,et al.  Major vault protein does not play a role in chemoresistance or drug localization in a non-small cell lung cancer cell line. , 2005, Biochemistry.

[25]  V. Kickhoefer,et al.  The 193-Kd Vault Protein, Vparp, Is a Novel Poly(Adp-Ribose) Polymerase , 1999, The Journal of cell biology.

[26]  V. Kickhoefer,et al.  The Telomerase/Vault-Associated Protein Tep1 Is Required for Vault RNA Stability and Its Association with the Vault Particle , 2001, The Journal of cell biology.

[27]  L. Chin,et al.  Short Dysfunctional Telomeres Impair Tumorigenesis in the INK4aΔ2/3 Cancer-Prone Mouse , 1999, Cell.

[28]  E. Wiemer,et al.  The Major Vault Protein Is a Novel Substrate for the Tyrosine Phosphatase SHP-2 and Scaffold Protein in Epidermal Growth Factor Signaling* , 2004, Journal of Biological Chemistry.

[29]  V. Kickhoefer,et al.  Vault Poly(ADP-Ribose) Polymerase Is Associated with Mammalian Telomerase and Is Dispensable for Telomerase Function and Vault Structure In Vivo , 2004, Molecular and Cellular Biology.

[30]  P. Sonneveld,et al.  Vaults: a ribonucleoprotein particle involved in drug resistance? , 2003, Oncogene.

[31]  J. Cigudosa,et al.  Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase–deficient mice and primary cells despite increased chromosomal instability , 2001, The Journal of cell biology.

[32]  V. Kickhoefer,et al.  The p80 homology region of TEP1 is sufficient for its association with the telomerase and vault RNAs, and the vault particle , 2005, Nucleic acids research.

[33]  P. Chambon,et al.  Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  D. Broccoli,et al.  p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. , 1999, Science.

[35]  K. Fung,et al.  Low-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is associated with increased LRP expression and altered subcellular drug distribution. , 2000, Toxicology and applied pharmacology.

[36]  P. Magee,et al.  The Alkylation of Nucleic Acids of Rat and Mouse In Vivo by the Carcinogen 1,2-Dimethylhydrazine , 1974, British Journal of Cancer.

[37]  N. Kedersha,et al.  Evidence that vault ribonucleoprotein particles localize to the nuclear pore complex. , 1993, Journal of cell science.

[38]  V. Kickhoefer,et al.  The La RNA-binding Protein Interacts with the Vault RNA and Is a Vault-associated Protein* , 2002, The Journal of Biological Chemistry.

[39]  V. Kickhoefer,et al.  Vaults Are Up-regulated in Multidrug-resistant Cancer Cell Lines* , 1998, The Journal of Biological Chemistry.

[40]  P. Sonneveld,et al.  Efflux Kinetics and Intracellular Distribution of Daunorubicin Are Not Affected by Major Vault Protein/Lung Resistance-Related Protein (Vault) Expression , 2004, Cancer Research.

[41]  A. Malkinson.  The genetic basis of susceptibility to lung tumors in mice. , 1989, Toxicology.

[42]  Richard A. Ashmun,et al.  Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF , 1997, Cell.

[43]  A. Malkinson,et al.  Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice. , 1983, Journal of the National Cancer Institute.

[44]  V. Kickhoefer,et al.  The M r 193 , 000 Vault Protein Is Up-Regulated in Multidrug-resistant Cancer Cell Lines 1 , 2000 .

[45]  L. Chin,et al.  Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation , 2000, Nature Genetics.

[46]  M. Blasco,et al.  Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis , 2000, Nature Genetics.

[47]  A. Mittelman,et al.  Differential susceptibility of four mouse strains to induction of multiple large-bowel neoplasms by 1,2-dimethylhydrazine. , 1974, Journal of the National Cancer Institute.

[48]  W. J. Burdette.  Carcinoma of the colon and antecedent epithelium. , 1970, Cancer research.

[49]  Hiroshi Suzuki,et al.  Parp‐1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane , 2003, Cancer science.

[50]  Lea Harrington,et al.  A Mammalian Telomerase-Associated Protein , 1997, Science.

[51]  J. Miller,et al.  Vinyl carbamate epoxide, a major strong electrophilic, mutagenic and carcinogenic metabolite of vinyl carbamate and ethyl carbamate (urethane). , 1993, Carcinogenesis.

[52]  V. Kickhoefer,et al.  Assembly of Vault-like Particles in Insect Cells Expressing Only the Major Vault Protein* , 2001, The Journal of Biological Chemistry.

[53]  V. Kickhoefer,et al.  Vaults and Telomerase Share a Common Subunit, TEP1* , 1999, The Journal of Biological Chemistry.

[54]  D. Shippen.  Telomeres and telomerases. , 1993, Current opinion in genetics & development.

[55]  E. Fiala.  Investigations into the metabolism and mode of action of the colon carcinogens 1,2‐dimethylhydrazine and azoxymethane , 1977, Cancer.

[56]  Lynda Chin,et al.  p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis , 1999, Cell.

[57]  Z. Herceg,et al.  Increased resistance to anticancer therapy of mouse cells lacking the poly(ADP-ribose) polymerase attributable to up-regulation of the multidrug resistance gene product P-glycoprotein. , 2000, Cancer research.

[58]  M. Hande,et al.  DNA Strand Break-Sensing Molecule Poly(ADP-Ribose) Polymerase Cooperates with p53 in Telomere Function, Chromosome Stability, and Tumor Suppression , 2001, Molecular and Cellular Biology.

[59]  T. Sugimura,et al.  Poly(ADP‐ribose) and carcinogenesis , 2003, Genes, chromosomes & cancer.

[60]  T. Sugimura,et al.  The response of Parp knockout mice against DNA damaging agents. , 2000, Mutation research.

[61]  M. Izquierdo,et al.  Vault-related resistance to anticancer drugs determined by the expression of the major vault protein LRP , 1998, Cytotechnology.

[62]  V. Kickhoefer,et al.  Disruption of the murine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. , 2002, Cancer research.

[63]  V. Kickhoefer,et al.  Telomerase-Associated Protein TEP1 Is Not Essential for Telomerase Activity or Telomere Length Maintenance In Vivo , 2000, Molecular and Cellular Biology.

[64]  V. Kickhoefer,et al.  Vault ribonucleoprotein particles from rat and bullfrog contain a related small RNA that is transcribed by RNA polymerase III. , 1993, The Journal of biological chemistry.

[65]  T. Mayhew,et al.  A simpler way of comparing the labelling densities of cellular compartments illustrated using data from VPARP and LAMP-1 immunogold labelling experiments , 2003, Histochemistry and Cell Biology.

[66]  Q. S. Wang,et al.  Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility. , 1998, Cancer letters.