Human Cpr (Cell Cycle Progression Restoration) Genes Impart a Far(-) Phenotype on Yeast Cells (original) (raw)

Abstract

Regulated cell cycle progression depends on the proper integration of growth control pathways with the basic cell cycle machinery. While many of the central molecules such as cyclins, CDKs, and CKIs are known, and many of the kinases and phosphatases that modify the CDKs have been identified, little is known about the additional layers of regulation that impinge upon these molecules. To identify new regulators of cell proliferation, we have selected for human and yeast cDNAs that when overexpressed were capable of specifically overcoming G(1) arrest signals from the cell cycle branch of the mating pheromone pathway, while still maintaining the integrity of the transcriptional induction branch. We have identified 13 human CPR (cell cycle progression restoration) genes and 11 yeast OPY (overproduction-induced pheromone-resistant yeast) genes that specifically block the G(1) arrest by mating pheromone. The CPR genes represent a variety of biochemical functions including a new cyclin, a tumor suppressor binding protein, chaperones, transcription factors, translation factors, RNA-binding proteins, as well as novel proteins. Several CPR genes require individual CLNs to promote pheromone resistance and those that require CLN3 increase the basal levels of Cln3 protein. Moreover, several of the yeast OPY genes have overlapping functions with the human CPR genes, indicating a possible conservation of roles.

Full Text

The Full Text of this article is available as a PDF (4.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baeuerle P. A., Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. doi: 10.1016/s0092-8674(00)81318-5. [DOI] [PubMed] [Google Scholar]
  2. Bertolino E., Reimund B., Wildt-Perinic D., Clerc R. G. A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif. J Biol Chem. 1995 Dec 29;270(52):31178–31188. doi: 10.1074/jbc.270.52.31178. [DOI] [PubMed] [Google Scholar]
  3. Caplan A. J., Langley E., Wilson E. M., Vidal J. Hormone-dependent transactivation by the human androgen receptor is regulated by a dnaJ protein. J Biol Chem. 1995 Mar 10;270(10):5251–5257. doi: 10.1074/jbc.270.10.5251. [DOI] [PubMed] [Google Scholar]
  4. Carey T. E., Van Dyke D. L., Worsham M. J. Nonrandom chromosome aberrations and clonal populations in head and neck cancer. Anticancer Res. 1993 Nov-Dec;13(6B):2561–2567. [PubMed] [Google Scholar]
  5. Chang F., Herskowitz I. Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2. Cell. 1990 Nov 30;63(5):999–1011. doi: 10.1016/0092-8674(90)90503-7. [DOI] [PubMed] [Google Scholar]
  6. Cross F. R. DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae. Mol Cell Biol. 1988 Nov;8(11):4675–4684. doi: 10.1128/mcb.8.11.4675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cross F. R. Starting the cell cycle: what's the point? Curr Opin Cell Biol. 1995 Dec;7(6):790–797. doi: 10.1016/0955-0674(95)80062-x. [DOI] [PubMed] [Google Scholar]
  8. Donzé O., Jagus R., Koromilas A. E., Hershey J. W., Sonenberg N. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J. 1995 Aug 1;14(15):3828–3834. doi: 10.1002/j.1460-2075.1995.tb00052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dorer R., Pryciak P. M., Hartwell L. H. Saccharomyces cerevisiae cells execute a default pathway to select a mate in the absence of pheromone gradients. J Cell Biol. 1995 Nov;131(4):845–861. doi: 10.1083/jcb.131.4.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dyer M. J., Nacheva E., Fischer P., Heward J. M., Labastide W., Karpas A. A new human T-cell lymphoma cell line (Karpas 384) of the T-cell receptor gamma/delta lineage with translocation t(7:14) (p13;q11.2). Leukemia. 1993 Jul;7(7):1047–1053. [PubMed] [Google Scholar]
  11. Elledge S. J., Davis R. W. Identification and isolation of the gene encoding the small subunit of ribonucleotide reductase from Saccharomyces cerevisiae: DNA damage-inducible gene required for mitotic viability. Mol Cell Biol. 1987 Aug;7(8):2783–2793. doi: 10.1128/mcb.7.8.2783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Epstein C. B., Cross F. R. Genes that can bypass the CLN requirement for Saccharomyces cerevisiae cell cycle START. Mol Cell Biol. 1994 Mar;14(3):2041–2047. doi: 10.1128/mcb.14.3.2041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fernandez-Sarabia M. J., Sutton A., Zhong T., Arndt K. T. SIT4 protein phosphatase is required for the normal accumulation of SWI4, CLN1, CLN2, and HCS26 RNAs during late G1. Genes Dev. 1992 Dec;6(12A):2417–2428. doi: 10.1101/gad.6.12a.2417. [DOI] [PubMed] [Google Scholar]
  14. Hanauske-Abel H. M., Park M. H., Hanauske A. R., Popowicz A. M., Lalande M., Folk J. E. Inhibition of the G1-S transition of the cell cycle by inhibitors of deoxyhypusine hydroxylation. Biochim Biophys Acta. 1994 Mar 31;1221(2):115–124. doi: 10.1016/0167-4889(94)90003-5. [DOI] [PubMed] [Google Scholar]
  15. Hanauske-Abel H. M., Slowinska B., Zagulska S., Wilson R. C., Staiano-Coico L., Hanauske A. R., McCaffrey T., Szabo P. Detection of a sub-set of polysomal mRNAs associated with modulation of hypusine formation at the G1-S boundary. Proposal of a role for eIF-5A in onset of DNA replication. FEBS Lett. 1995 Jun 12;366(2-3):92–98. doi: 10.1016/0014-5793(95)00493-s. [DOI] [PubMed] [Google Scholar]
  16. Harper J. W., Elledge S. J. Cdk inhibitors in development and cancer. Curr Opin Genet Dev. 1996 Feb;6(1):56–64. doi: 10.1016/s0959-437x(96)90011-8. [DOI] [PubMed] [Google Scholar]
  17. Hartwell L. H., Mortimer R. K., Culotti J., Culotti M. Genetic Control of the Cell Division Cycle in Yeast: V. Genetic Analysis of cdc Mutants. Genetics. 1973 Jun;74(2):267–286. doi: 10.1093/genetics/74.2.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell. 1995 Jan 27;80(2):187–197. doi: 10.1016/0092-8674(95)90402-6. [DOI] [PubMed] [Google Scholar]
  19. Higgins K. A., Perez J. R., Coleman T. A., Dorshkind K., McComas W. A., Sarmiento U. M., Rosen C. A., Narayanan R. Antisense inhibition of the p65 subunit of NF-kappa B blocks tumorigenicity and causes tumor regression. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9901–9905. doi: 10.1073/pnas.90.21.9901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Horecka J., Sprague G. F., Jr Identification and characterization of FAR3, a gene required for pheromone-mediated G1 arrest in Saccharomyces cerevisiae. Genetics. 1996 Nov;144(3):905–921. doi: 10.1093/genetics/144.3.905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Inaba T., Oku N., Gotoh H., Murakami S., Oku N., Itoh K., Ura Y., Nakanishi S., Shimazaki C., Nakagawa M. Philadelphia chromosome positive precursor B-cell acute lymphoblastic leukemia with a translocation t(2;14)(p13;q32). Leukemia. 1991 Aug;5(8):719–722. [PubMed] [Google Scholar]
  22. Kang H. A., Hershey J. W. Effect of initiation factor eIF-5A depletion on protein synthesis and proliferation of Saccharomyces cerevisiae. J Biol Chem. 1994 Feb 11;269(6):3934–3940. [PubMed] [Google Scholar]
  23. Klopotowski T., Wiater A. Synergism of aminotriazole and phosphate on the inhibition of yeast imidazole glycerol phosphate dehydratase. Arch Biochem Biophys. 1965 Dec;112(3):562–566. doi: 10.1016/0003-9861(65)90096-2. [DOI] [PubMed] [Google Scholar]
  24. Lazaris-Karatzas A., Montine K. S., Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature. 1990 Jun 7;345(6275):544–547. doi: 10.1038/345544a0. [DOI] [PubMed] [Google Scholar]
  25. Lee K. S., Hines L. K., Levin D. E. A pair of functionally redundant yeast genes (PPZ1 and PPZ2) encoding type 1-related protein phosphatases function within the PKC1-mediated pathway. Mol Cell Biol. 1993 Sep;13(9):5843–5853. doi: 10.1128/mcb.13.9.5843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Liu H., Krizek J., Bretscher A. Construction of a GAL1-regulated yeast cDNA expression library and its application to the identification of genes whose overexpression causes lethality in yeast. Genetics. 1992 Nov;132(3):665–673. doi: 10.1093/genetics/132.3.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Luke M. M., Sutton A., Arndt K. T. Characterization of SIS1, a Saccharomyces cerevisiae homologue of bacterial dnaJ proteins. J Cell Biol. 1991 Aug;114(4):623–638. doi: 10.1083/jcb.114.4.623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lyons D. M., Mahanty S. K., Choi K. Y., Manandhar M., Elion E. A. The SH3-domain protein Bem1 coordinates mitogen-activated protein kinase cascade activation with cell cycle control in Saccharomyces cerevisiae. Mol Cell Biol. 1996 Aug;16(8):4095–4106. doi: 10.1128/mcb.16.8.4095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Matsuoka S., Edwards M. C., Bai C., Parker S., Zhang P., Baldini A., Harper J. W., Elledge S. J. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 1995 Mar 15;9(6):650–662. doi: 10.1101/gad.9.6.650. [DOI] [PubMed] [Google Scholar]
  30. Nacheva E., Holloway T., Carter N., Grace C., White N., Green A. R. Characterization of 20q deletions in patients with myeloproliferative disorders or myelodysplastic syndromes. Cancer Genet Cytogenet. 1995 Apr;80(2):87–94. doi: 10.1016/0165-4608(94)00150-a. [DOI] [PubMed] [Google Scholar]
  31. Narayanan R., Higgins K. A., Perez J. R., Coleman T. A., Rosen C. A. Evidence for differential functions of the p50 and p65 subunits of NF-kappa B with a cell adhesion model. Mol Cell Biol. 1993 Jun;13(6):3802–3810. doi: 10.1128/mcb.13.6.3802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nash R., Tokiwa G., Anand S., Erickson K., Futcher A. B. The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. EMBO J. 1988 Dec 20;7(13):4335–4346. doi: 10.1002/j.1460-2075.1988.tb03332.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nolan G. P., Ghosh S., Liou H. C., Tempst P., Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell. 1991 Mar 8;64(5):961–969. doi: 10.1016/0092-8674(91)90320-x. [DOI] [PubMed] [Google Scholar]
  34. Nomoto S., Nakayama N., Arai K., Matsumoto K. Regulation of the yeast pheromone response pathway by G protein subunits. EMBO J. 1990 Mar;9(3):691–696. doi: 10.1002/j.1460-2075.1990.tb08161.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Oehlen L. J., Cross F. R. G1 cyclins CLN1 and CLN2 repress the mating factor response pathway at Start in the yeast cell cycle. Genes Dev. 1994 May 1;8(9):1058–1070. doi: 10.1101/gad.8.9.1058. [DOI] [PubMed] [Google Scholar]
  36. Oh S., Iwahori A., Kato S. Human cDNA encoding DnaJ protein homologue. Biochim Biophys Acta. 1993 Jul 18;1174(1):114–116. doi: 10.1016/0167-4781(93)90104-l. [DOI] [PubMed] [Google Scholar]
  37. Overhauser J., Mitchell H. F., Zackai E. H., Tick D. B., Rojas K., Muenke M. Physical mapping of the holoprosencephaly critical region in 18p11.3. Am J Hum Genet. 1995 Nov;57(5):1080–1085. [PMC free article] [PubMed] [Google Scholar]
  38. Pardee A. B. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1286–1290. doi: 10.1073/pnas.71.4.1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Peter M., Gartner A., Horecka J., Ammerer G., Herskowitz I. FAR1 links the signal transduction pathway to the cell cycle machinery in yeast. Cell. 1993 May 21;73(4):747–760. doi: 10.1016/0092-8674(93)90254-n. [DOI] [PubMed] [Google Scholar]
  40. Peter M., Herskowitz I. Direct inhibition of the yeast cyclin-dependent kinase Cdc28-Cln by Far1. Science. 1994 Aug 26;265(5176):1228–1231. doi: 10.1126/science.8066461. [DOI] [PubMed] [Google Scholar]
  41. Peterson J., Zheng Y., Bender L., Myers A., Cerione R., Bender A. Interactions between the bud emergence proteins Bem1p and Bem2p and Rho-type GTPases in yeast. J Cell Biol. 1994 Dec;127(5):1395–1406. doi: 10.1083/jcb.127.5.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Raabe T., Manley J. L. A human homologue of the Escherichia coli DnaJ heat-shock protein. Nucleic Acids Res. 1991 Dec 11;19(23):6645–6645. doi: 10.1093/nar/19.23.6645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schild D., Brake A. J., Kiefer M. C., Young D., Barr P. J. Cloning of three human multifunctional de novo purine biosynthetic genes by functional complementation of yeast mutations. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2916–2920. doi: 10.1073/pnas.87.8.2916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schnier J., Schwelberger H. G., Smit-McBride Z., Kang H. A., Hershey J. W. Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1991 Jun;11(6):3105–3114. doi: 10.1128/mcb.11.6.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Steinkasserer A., Jones T., Sheer D., Koettnitz K., Hauber J., Bevec D. The eukaryotic cofactor for the human immunodeficiency virus type 1 (HIV-1) rev protein, eIF-5A, maps to chromosome 17p12-p13: three eIF-5A pseudogenes map to 10q23.3, 17q25, and 19q13.2. Genomics. 1995 Feb 10;25(3):749–752. doi: 10.1016/0888-7543(95)80025-h. [DOI] [PubMed] [Google Scholar]
  46. Su L. K., Burrell M., Hill D. E., Gyuris J., Brent R., Wiltshire R., Trent J., Vogelstein B., Kinzler K. W. APC binds to the novel protein EB1. Cancer Res. 1995 Jul 15;55(14):2972–2977. [PubMed] [Google Scholar]
  47. Sutton A., Immanuel D., Arndt K. T. The SIT4 protein phosphatase functions in late G1 for progression into S phase. Mol Cell Biol. 1991 Apr;11(4):2133–2148. doi: 10.1128/mcb.11.4.2133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Trecca D., Guerrini L., Fracchiolla N. S., Pomati M., Baldini L., Maiolo A. T., Neri A. Identification of a tumor-associated mutant form of the NF-kappaB RelA gene with reduced DNA-binding and transactivating activities. Oncogene. 1997 Feb 20;14(7):791–799. doi: 10.1038/sj.onc.1200895. [DOI] [PubMed] [Google Scholar]
  49. Tyers M., Futcher B. Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes. Mol Cell Biol. 1993 Sep;13(9):5659–5669. doi: 10.1128/mcb.13.9.5659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Tyers M., Tokiwa G., Futcher B. Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J. 1993 May;12(5):1955–1968. doi: 10.1002/j.1460-2075.1993.tb05845.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Valtz N., Peter M., Herskowitz I. FAR1 is required for oriented polarization of yeast cells in response to mating pheromones. J Cell Biol. 1995 Nov;131(4):863–873. doi: 10.1083/jcb.131.4.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Voorter C., Joos S., Bringuier P. P., Vallinga M., Poddighe P., Schalken J., du Manoir S., Ramaekers F., Lichter P., Hopman A. Detection of chromosomal imbalances in transitional cell carcinoma of the bladder by comparative genomic hybridization. Am J Pathol. 1995 Jun;146(6):1341–1354. [PMC free article] [PubMed] [Google Scholar]
  53. Whiteway M., Hougan L., Thomas D. Y. Overexpression of the STE4 gene leads to mating response in haploid Saccharomyces cerevisiae. Mol Cell Biol. 1990 Jan;10(1):217–222. doi: 10.1128/mcb.10.1.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wittenberg C., Sugimoto K., Reed S. I. G1-specific cyclins of S. cerevisiae: cell cycle periodicity, regulation by mating pheromone, and association with the p34CDC28 protein kinase. Cell. 1990 Jul 27;62(2):225–237. doi: 10.1016/0092-8674(90)90361-h. [DOI] [PubMed] [Google Scholar]
  55. Yaglom J. A., Goldberg A. L., Finley D., Sherman M. Y. The molecular chaperone Ydj1 is required for the p34CDC28-dependent phosphorylation of the cyclin Cln3 that signals its degradation. Mol Cell Biol. 1996 Jul;16(7):3679–3684. doi: 10.1128/mcb.16.7.3679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zhang J., Chang C. C., Lombardi L., Dalla-Favera R. Rearranged NFKB2 gene in the HUT78 T-lymphoma cell line codes for a constitutively nuclear factor lacking transcriptional repressor functions. Oncogene. 1994 Jul;9(7):1931–1937. [PubMed] [Google Scholar]
  57. Zhang L., Zhou W., Velculescu V. E., Kern S. E., Hruban R. H., Hamilton S. R., Vogelstein B., Kinzler K. W. Gene expression profiles in normal and cancer cells. Science. 1997 May 23;276(5316):1268–1272. doi: 10.1126/science.276.5316.1268. [DOI] [PubMed] [Google Scholar]
  58. Zhou Z., Elledge S. J. Isolation of crt mutants constitutive for transcription of the DNA damage inducible gene RNR3 in Saccharomyces cerevisiae. Genetics. 1992 Aug;131(4):851–866. doi: 10.1093/genetics/131.4.851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Zhu L., van den Heuvel S., Helin K., Fattaey A., Ewen M., Livingston D., Dyson N., Harlow E. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev. 1993 Jul;7(7A):1111–1125. doi: 10.1101/gad.7.7a.1111. [DOI] [PubMed] [Google Scholar]
  60. van den Heuvel S., Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993 Dec 24;262(5142):2050–2054. doi: 10.1126/science.8266103. [DOI] [PubMed] [Google Scholar]