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 Article
  • Published:

LKB1 — A master tumour suppressor of the small intestine and beyond

Nature Reviews Cancer volume 2, pages 529–535 (2002)Cite this article

Key Points

  • Peutz–Jeghers syndrome (PJS) is an autosomal polyposis disorder that is characterized by cancer predisposition at a young age. It is associated with inactivating mutations in the LKB1 gene.

  • Different hamartomatous polyposis syndromes are associated with different types of genetic defects. PJS is characterized by gastrointestinal hamartomas that have a smooth-muscle core.

  • LKB1 is required for normal fetal development and is present in apoptotic intestinal cells. LKB1 has been shown to be involved in p53-mediated apoptosis. LKB1 phosphorylates p53 at low levels, which might be required for p53 activation.

  • LKB1 has also been shown to control cell proliferation. It interacts with the chromatin remodelling protein brahma-related gene-1 (BRG1), and also with the cell-cycle regulatory proteins LKB1-interacting protein 1 (LIP1) and WAF1.

  • LKB1 is therefore an important tumour suppressor that might be developed as a cancer therapeutic target.

Abstract

Peutz–Jeghers syndrome (PJS) is a rare, inherited intestinal polyposis syndrome that is associated with a significantly increased risk of several types of cancer — particularly those of the gastrointestinal and reproductive systems. Most cases of PJS have been associated with loss-of-function mutations in the ubiquitously expressed LKB1 gene, which encodes a serine/ threonine kinase. Recent studies have begun to illustrate the molecular mechanisms by which LKB1 functions as an important new tumour suppressor.

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: Schematic diagram of the LKB1 gene.
Figure 2: Possible model for LKB1 function in apoptosis.
Figure 3: Possible model for LKB1 in tumour suppression.

Similar content being viewed by others

References

  1. Coit, D. G. in Cancer: Principles & Practice of Oncology (eds DeVita, V. T., Hellman, S. & Rosenberg, S. A.) 1204–1216 (Lippincott Williams & Wilkins, Philadelphia, 2001).

    Google Scholar 

  2. Peutz, J. D. A. Over een zeer Merkwaardige, gecombinerde familiare polyposis van de slijmvliezen van den tractus intestinalis met die van de neuskeelholte en gepaard met elgenaardige pigmentaties van huid en slijmvlisen. Ned. Tijdschr. Geneeskd. 10, 134 (1921).

    Google Scholar 

  3. Jeghers, H., McKusick, V. A. & Katz, K. H. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits. N. Engl. J. Med. 241, 993–1005 (1949).

    Article  CAS  Google Scholar 

  4. Bartholomew, L. G., Dahlin, D. C. & Waugh, J. M. Intestinal polyposis associated with mucocutaneous melanin pigmentation (Peutz–Jeghers syndrome). Gastroenterology 32, 434–451 (1957).

    CAS  PubMed  Google Scholar 

  5. Bartholomew, L. G., Moore, C. E., Dahlin, D. C. & Waugh, J. M. Intestinal polyposis associated with mucocutaneous pigmentation. Surg. Gyn. Obstet. 115, 1–11 (1962).

    CAS  Google Scholar 

  6. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998).One of the first papers that identifies inactivating mutations in LKB1 as the molecular basis for Peutz–Jeghers syndrome.

    Article  CAS  Google Scholar 

  7. Jenne, D. E. et al. Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet. 18, 38–43 (1998).One of the first papers that identifies inactivating mutations in LKB1 as the molecular basis for Peutz–Jeghers syndrome, and describes expression patterns in human fetuses and adults.

    Article  CAS  Google Scholar 

  8. Olschwang, S., Boisson, C. & Thomas, G. Peutz–Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma. J. Med. Genet. 38, 356–360 (2001).

    Article  CAS  Google Scholar 

  9. Hemminki, A. et al. Localization of a susceptibility locus for Peutz–Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nature Genet. 15, 87–90 (1997).

    Article  CAS  Google Scholar 

  10. McAllister, A. J. & Richards, K. F. Peutz–Jeghers syndrome: experience with twenty patients in five generations. Am. J. Surg. 134, 717–720 (1977).

    Article  CAS  Google Scholar 

  11. Mehenni, H. et al. Peutz–Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am. J. Hum. Genet. 61, 1327–1334 (1997).

    Article  CAS  Google Scholar 

  12. Giardiello, F. M. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119, 1447–1453 (2000).A statistical analysis of data from published reports on incidence of cancer in patients with Peutz–Jeghers syndrome, showing greatly increased risk for several types of cancer.

    Article  CAS  Google Scholar 

  13. Boardman, L. A. et al. Increased risk for cancer in patients with the Peutz–Jeghers syndrome. Ann. Intern. Med. 128, 896–899 (1998).

    Article  CAS  Google Scholar 

  14. Giardiello, F. M. et al. Increased risk of cancer in the Peutz–Jeghers syndrome. N. Engl. J. Med. 316, 1511–1514 (1987).

    Article  CAS  Google Scholar 

  15. Spigelman, A. D., Murday, V. & Phillips, R. K. Cancer and the Peutz–Jeghers syndrome. Gut 30, 1588–1590 (1989).

    Article  CAS  Google Scholar 

  16. Entius, M. M. et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz–Jeghers syndrome. J. Clin. Pathol. 54, 126–131 (2001).

    Article  CAS  Google Scholar 

  17. Gruber, S. B. et al. Pathogenesis of adenocarcinoma in Peutz–Jeghers syndrome. Cancer Res. 58, 5267–5270 (1998).

    CAS  PubMed  Google Scholar 

  18. Jiang, C. Y. et al. STK11/LKB1 germline mutations are not identified in most Peutz–Jeghers syndrome patients. Clin. Genet. 56, 136–141 (1999).

    Article  CAS  Google Scholar 

  19. Miyaki, M. et al. Somatic mutations of LKB1 and β-catenin genes in gastrointestinal polyps from patients with Peutz–Jeghers syndrome. Cancer Res. 60, 6311–6313 (2000).

    CAS  PubMed  Google Scholar 

  20. Miyoshi, H. et al. Gastrointestinal hamartomatous polyposis in lkb1 heterozygous knockout mice. Cancer Res. 62, 2261–2266 (2002).The first publication that describes the gastrointestinal polyposis that is similar to Peutz–Jeghers syndrome, which occurs in Lkb1+/− mice. No evidence of LOH was found in the polyps, indicating that haploinsufficiency of Lkb1 can cause polyposis.

    CAS  PubMed  Google Scholar 

  21. Howe, J. R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).

    Article  CAS  Google Scholar 

  22. Takaku, K. et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 59, 6113–6117 (1999).

    CAS  PubMed  Google Scholar 

  23. Howe, J. R. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genet. 28, 184–187 (2001).

    Article  CAS  Google Scholar 

  24. Wirtzfeld, D. A., Petrelli, N. J. & Rodriguez-Bigas, M. A. Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann. Surg. Oncol. 8, 319–327 (2001).

    Article  CAS  Google Scholar 

  25. Xu, X. et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 19, 1868–1874 (2000).

    Article  CAS  Google Scholar 

  26. Jacoby, R. F. et al. A juvenile polyposis tumor suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria. Gastroenterology 112, 1398–1403 (1997).

    Article  CAS  Google Scholar 

  27. Kinzler, K. W. & Vogelstein, B. Landscaping the cancer terrain. Science 280, 1036–1037 (1998).A proposal that polyps, such as in the case with juvenile polyposis syndrome, can be generated not as a result of mutations in the epithelial cells, but as a result of mutations in the stromal-cell population — a 'landscaping defect'.

    Article  CAS  Google Scholar 

  28. Woodford-Richens, K. et al. Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium. Cancer Res. 60, 2477–2482 (2000).

    CAS  PubMed  Google Scholar 

  29. Wang, Z. J. et al. Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz–Jeghers' syndrome provides evidence for a hamartoma- (adenoma)-carcinoma sequence. J. Pathol. 188, 9–13 (1999).Evidence that LOH of LKB1 occurs in the epithelial cells of PJS polyps, and an example of a hamartoma with adenomatous and carcinomatous lesions due to loss of LKB1 , indicating possible progression from hamartomas to cancer.

    Article  CAS  Google Scholar 

  30. Day, D. W. The adenoma-carcinoma sequence. Scand. J. Gastroenterol. 104 (Suppl.), 99–107 (1984).

    CAS  Google Scholar 

  31. Su, J. Y., Erikson, E. & Maller, J. L. Cloning and characterization of a novel serine/threonine protein kinase expressed in early Xenopus embryos. J. Biol. Chem. 271, 14430–14437 (1996).

    Article  CAS  Google Scholar 

  32. Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988).

    Article  CAS  Google Scholar 

  33. Collins, S. P., Reoma, J. L., Gamm, D. M. & Uhler, M. D. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J. 345, 673–680 (2000).

    Article  CAS  Google Scholar 

  34. Karuman, P. et al. The Peutz–Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol. Cell 7, 1307–1319 (2001).Shows elevated LKB1 expression in dying intestinal epithelial cells, and indicates a role for LKB1 in apoptosis in cultured cells and in the intestine. p53 is shown to be a crucial mediator of LKB1-induced apoptosis.

    Article  CAS  Google Scholar 

  35. Nezu, J., Oku, A. & Shimane, M. Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz–Jeghers syndrome patients. Biochem. Biophys. Res. Commun. 261, 750–755 (1999).

    Article  CAS  Google Scholar 

  36. Smith, D. P., Spicer, J., Smith, A., Swift, S. & Ashworth, A. The mouse Peutz–Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase. Hum. Mol. Genet. 8, 1479–1485 (1999).

    Article  CAS  Google Scholar 

  37. Sapkota, G. P. et al. Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz–Jeghers cancer syndrome. Biochem. J. 362, 481–490 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sapkota, G. P. et al. Phosphorylation of the protein kinase mutated in Peutz–Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. J. Biol. Chem. 276, 19469–19482 (2001).Evidence that overexpressed LKB1 is phosphorylated by RSK and PKA in EGF- and forskolin-stimulated cells, respectively, and that LKB1 is farnesylated. Phosphorylation or farnesylation of LKB1 might be crucial for its growth-suppressive activity.

    Article  CAS  Google Scholar 

  39. Wang, Z. J. et al. Germline mutations of the LKB1 (STK11) gene in Peutz–Jeghers patients. J. Med. Genet. 36, 365–368 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Young, R. H., Welch, W. R., Dickersin, G. R. & Scully, R. E. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and four with adenoma malignum of the cervix. Cancer 50, 1384–1402 (1982).

    Article  CAS  Google Scholar 

  41. Rowan, A. et al. In situ analysis of LKB1/STK11 mRNA expression in human normal tissues and tumours. J. Pathol. 192, 203–206 (2000).

    Article  CAS  Google Scholar 

  42. Potten, C. S. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos. Trans. R. Soc. Lond. B Biol. Sci. 353, 821–830 (1998).

    Article  CAS  Google Scholar 

  43. Ylikorkala, A. et al. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293, 1323–1326 (2001).First paper describing the Lkb1−/− embryonic-lethal phenotype. Lkb1−/− embryos showed dysregulation of VEGF expression and decreased vascularization.

    Article  CAS  Google Scholar 

  44. Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16, 64–67 (1997).

    Article  CAS  Google Scholar 

  45. Luukko, K., Ylikorkala, A., Tiainen, M. & Makela, T. P. Expression of LKB1 and PTEN tumor suppressor genes during mouse embryonic development. Mech. Dev. 83, 187–190 (1999).

    Article  CAS  Google Scholar 

  46. Fenlon, J. W. Case report with angiographic evaluation. Radiology 103, 595–596 (1972).

    Article  CAS  Google Scholar 

  47. Clarke, A. R., Gledhill, S., Hooper, M. L., Bird, C. C. & Wyllie, A. H. p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following γ-irradiation. Oncogene 9, 1767–1773 (1994).

    CAS  PubMed  Google Scholar 

  48. Merritt, A. J. et al. The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res. 54, 614–617 (1994).

    CAS  PubMed  Google Scholar 

  49. Tiainen, M., Ylikorkala, A. & Makela, T. P. Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Proc. Natl Acad. Sci. USA 96, 9248–9251 (1999).First paper showing that LKB1 , when overexpressed, can induce cell-cycle arrest in certain types of cell line.

    Article  CAS  Google Scholar 

  50. Furnari, F. B., Lin, H., Huang, H. S. & Cavenee, W. K. Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc. Natl Acad. Sci. USA 94, 12479–12484 (1997).

    Article  CAS  Google Scholar 

  51. Tiainen, M., Vaahtomeri, K., Ylikorkala, A. & Makela, T. P. Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum. Mol. Genet. 11, 1497–1504 (2002).

    Article  CAS  Google Scholar 

  52. Marignani, P. A., Kanai, F. & Carpenter, C. L. LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. J. Biol. Chem. 276, 32415–32418 (2001).

    Article  CAS  Google Scholar 

  53. Dunaief, J. L. et al. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79, 119–130 (1994).

    Article  CAS  Google Scholar 

  54. Smith, D. P. et al. LIP1, a cytoplasmic protein functionally linked to the Peutz–Jeghers syndrome kinase LKB1. Hum. Mol. Genet. 10, 2869–2877 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

J. Y. and D. C. C are supported in part by National Cancer Institute grants. L. I. Y. is supported by a fellowship from the American Cancer Society.

Author information

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Lina I. Yoo & Junying Yuan

  2. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Daniel C. Chung

Authors
  1. Lina I. Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel C. Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junying Yuan.

Related links

Related links

DATABASES

Cancer.gov

breast cancer

cervical cancer

colorectal cancer

gastric cancer

lung cancer

ovarian cancer

pancreatic cancer

small-intestinal cancer

testicular cancer

uterine cancer

LocusLink

BCL2

BMPR1A

BRG1

EGF

LIP1

Lkb1

LKB1

p53

PKA

Pten

PTEN

RB

RSK

Smad4

SMAD4

TGF-β

Trp53

VEGF

WAF1

Medscape DrugInfo

doxorubicin

5-fluorouracil

paclitaxel

vincristine

OMIM

Cowden's disease

juvenile polyposis syndrome

Peutz–Jeghers syndrome

FURTHER INFORMATION

NCI Seer database

NCBI BLAST Search program

The Network for Peutz Jeghers and Juvenile Polyposis Syndrome

PSORT II Prediction

Glossary

HAMARTOMA

A benign overgrowth of tissue that is composed of cells that are normally present at that site. In the gastrointestinal tract, hamartomas typically have a marked expansion of the muscular and fibrous tissue layer.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome that carries the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

FLUORESCENT IN SITU HYBRIDIZATION

(FISH). A technique that is used to detect nucleic acids in cells or tissues by using probes that are coupled to a fluorescent dye.

NON-CELL AUTONOMOUS

Describes a signal that is is passed from one cell to another.

PRENYLATION

The covalent attachment of a hydrophobic prenyl group to a molecule. This can result in membrane localization.

PYKNOTIC

Describes a condensed, misshapen nucleus, that is characteristic of an apoptotic cell.

DOMINANT-NEGATIVE MUTANT

A non-functional mutant protein that competes with the normal, non-mutated protein, blocking its activity.

FORSKOLIN

A vasodilating drug that is produced by the Coleus forskohlii plant. It activates adenylate cyclase, leading to elevated cyclic AMP levels.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoo, L., Chung, D. & Yuan, J. LKB1 — A master tumour suppressor of the small intestine and beyond. Nat Rev Cancer 2, 529–535 (2002). https://doi.org/10.1038/nrc843

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc843

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing