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.

  • Original Paper
  • Published:

SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia

Oncogene volume 22, pages 2823–2835 (2003)Cite this article

Abstract

Regions of hypoxia are a hallmark of solid tumors. Tumor cells modulate the regulation of specific genes allowing adaptation and survival in the harsh hypoxic environment. We have identified SKIP3, a novel human kinase-like gene, which is overexpressed in multiple human tumors and is regulated by hypoxia. SKIP3 is an ortholog of the Drosophila tribbles, rat NIPK, dog C5FW, and human C8FW genes. Drosophila tribbles is involved in slowing cell-cycle progression during Drosophila development, but little is known regarding the function or tissue distribution of the vertebrate orthologs. We show that the normal tissue expression of SKIP3 is confined to human liver, while multiple primary human lung, colon, and breast tumors express high levels of SKIP3 transcript. Endogenous SKIP3 protein accumulates within 48 h under hypoxic growth conditions in HT-29 and PC-3 cells, with upregulation of the SKIP3 mRNA transcript by 72 h. We identified activating transcription factor 4 (ATF4) as a SKIP3-binding partner using the yeast-two-hybrid assay. Coexpression of SKIP3 and ATF4 showed that SKIP3 is associated with the proteolysis of ATF4, which can be blocked using a proteosome inhibitor. These results indicate that SKIP3 may be an important participant in tumor cell growth.

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
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Ausserer WA, Bourrat-Floeck B, Green CJ, Laderoute KR and Sutherland RM . (1994). Mol. Cell. Biol., 14, 5032–5042.

  • Butscher WG, Powers C, Olive M, Vinson C and Gardner K . (1998). J. Biol. Chem., 273, 552–560.

  • Eddy SR . (1996). Curr. Opin. Struct. Biol., 6, 361–365.

  • Estes SD, Stoler DL and Anderson GR . (1995). Exp. Cell Res., 220, 47–54.

  • Fafournoux P, Bruhat A and Jousse C . (2000). Biochem. J., 351, 1–12.

  • Fawcett TW, Martindale JL, Guyton KZ, Hai T and Holbrook NJ . (1999). Biochem. J., 339, 135–141.

  • Gachon F, Gaudray G, Thebault S, Basbous J, Koffi JA, Devaux C and Mesnard J . (2001). FEBS Lett., 502, 57–62.

  • Grosshans J and Wieschaus E . (2000). Cell, 101, 523–531.

  • Hai T and Curran T . (1991). Proc. Nat. Acad. Sci. USA, 88, 3720–3724.

  • Hai T and Hartman MG . (2001). Gene, 273, 1–11.

  • Hanks SK and Hunter T . (1995). FASEB J., 9, 576–596.

  • He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM and Alam J . (2001). J. Biol. Chem., 276, 20858–20865.

  • Hewes RS, Schaefer AM and Taghert PH . (2000). Genetics, 155, 1711–1723.

  • Hockel M and Vaupel P . (2001). J. Nat. Cancer Inst., 93, 266–276.

  • Karpinski BA, Morle GD, Huggenvik J, Uhler MD and Leiden JM . (1992). Proc. Nat. Acad. Sci. USA, 89, 4820–4824.

  • Kato Y, Koike Y, Tomizawa K, Ogawa S, Hosaka K, Tanaka S and Kato T . (1999). Mol. Cell. Endocrinol., 154, 151–159.

  • Kawai T, Matsumoto M, Takeda K, Sanjo H and Akira S . (1998). Mol. Cell. Biol., 18, 1642–1651.

  • Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ and Riggins GJ . (2001). J. Nat. Cancer Inst., 93, 1337–1343.

  • Lassot I, Segeral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R and Margottin-Goguet F . (2001). Mol. Cell. Biol., 21, 2192–2202.

  • Liang G and Hai T . (1997). J. Biol. Chem., 272, 24088–24095.

  • Masuoka HC and Townes TM . (2002). Blood, 99, 736–745.

  • Mata J, Curado S, Ephrussi A and Rorth P . (2000). Cell, 101, 511–522.

  • Mayumi-Matsuda K, Kojima S, Suzuki H and Sakata T . (1999). Biochem. Biophys. Res. Commun., 258, 260–264.

  • Nishizawa M and Nagata S . (1992). FEBS Lett., 299, 36–38.

  • Novoa I, Zeng H, Harding HP and Ron D . (2001). J. Cell Biol., 153, 1011–1022.

  • Reddy TR, Tang H, Li X and Wong-Staal F . (1997). Oncogene, 14, 2785–2792.

  • Rorth P, Szabo K and Texido G . (2000). Mol. Cell, 6, 23–30.

  • Saramaki OR, Savinainen KJ, Nupponen NN, Bratt O and Visakorpi T . (2001). Cancer Genet. Cytogenet., 128, 31–34.

  • Seher TC and Leptin M . (2000). Curr. Biol., 10, 623–629.

  • Semenza GL . (2000). Genes and Dev., 14, 1983–1991.

  • Tang K, Finley Jr RL, Nie D and Honn KV . (2000). Biochemistry, 39, 3185–3191.

  • Vallejo M, Ron D, Miller CP and Habener JF . (1993). Proc. Nat. Acad. Sci. USA, 90, 4679–4683.

  • Vinson CR, Hai T and Boyd SM . (1993). Genes Dev., 7, 1047–1058.

  • Wadle A, Thiel G, Mischo A, Jung V, Pfreundschuh M and Renner C . (2001). Oncogene, 20, 5920–5929.

  • Wilcox JN . (1993). J. Histochem. Cytochem., 41, 1725–1733.

  • Wilkin F, Suarez-Huerta N, Robaye B, Peetermans J, Libert F, Dumont JE and Maenhaut C . (1997). Eur. J. Biochem., 248, 660–668.

  • Yao KS, Clayton M and O'Dwyer PJ . (1995). J. Nat. Cancer Inst., 87, 117–122.

  • Yao KS, Xanthoudakis S, Curran T and O'Dwyer PJ . (1994). Mol. Cell. Biol., 14, 5997–6003.

Download references

Acknowledgements

We thank Marc Payton for providing the isolated total RNA from primary tumor samples for the TaqMan RT–PCR analysis and Tammy L Bush for providing the xenograft tumor material.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, 91320, CA, USA

    Alex J Bowers & John F Boylan

  2. Department of Pathology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, 91320, CA, USA

    Sheila Scully

Authors
  1. Alex J Bowers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheila Scully
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John F Boylan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John F Boylan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bowers, A., Scully, S. & Boylan, J. SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia. Oncogene 22, 2823–2835 (2003). https://doi.org/10.1038/sj.onc.1206367

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206367

Keywords

This article is cited by

Search

Advanced search

Quick links