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.

  • Letter to the Editor
  • Published:

Pleiotropic p27Kip1, BCR-ABL and leukemic stem cell: the trio in concert

Leukemia volume 21, pages 2559–2561 (2007)Cite this article

The mammalian cyclin-dependent kinase inhibitor (CDKI) p27 is a potent regulator of cell cycle arresting transition from G1 to S phase. In contrast to earlier opinion of mere cytoplasmic incapacitation of p27, there is a growing body of evidence suggesting that p27 could be transformed from a native CDKI into a dynamic oncoprotein at the expense of its extranuclear localization in leukemic cells. Emerging concepts also indicate that there are certain resident leukemic stem cells (LSC) in bone marrow milieu, which possess exuberant self-renewal characteristics and they eventually lead to conventional therapeutic recalcitrance. Given that BCR-ABL-containing CD34+ cells successfully persist in chronic myeloid leukemia (CML) patients with cytogenetic remission under imatinib, it is necessary to elucidate additional incongruous molecular program that might have significant therapeutic implications. In this connection, considering the functional nexus among p27, BCR-ABL and a transmembrane glycoprotein CD44 in the regulation of homing, engraftment and proliferation of LSCs together with the recent findings that p27 can promote cellular migration and metastasis in several other malignancies,1, 2, 3, 4 it could be pertinent to address the possibilities of p27 pleiotropism in regenerative and preventive medicine.

During G0- to S-phase transition, p27 proteolysis requires intact p27-cyclin-cdk trimeric motif. Cdk2-dependent phosphorylation of p27 at T187 promotes Skp1-Cul1-F-box (SCFSkp2) ubiquitin Ligase-mediated degradation of p27. In early G1 T187-independent p27, proteolysis can also take place that involves Skp2-dependent and Skp2-independent mechanisms. However, proteolysis of cytoplasmic pool of p27 in G1 sometimes involves a different Kip1 ubiquitination promoting complex ubiquitin ligase. Furthermore, in early G1, phosphatidylinositol-3-kinase (PI3K)-dependent phosphorylation at T157 on the nuclear localization signal of p27 promotes cytoplasmic sequestration. In addition, molecular control of transcription, mRNA stabilization and protein degradation might all act in concert to impinge on the biological functions of p27.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Williams DA, Cancelas JA . Leukemia: niche retreats for stem cells. Nature 2006; 444: 827–828.

    Article  CAS  Google Scholar 

  2. Gadhoum Z, Leibovitch MP, Qi J, Dumenil D, Durand L, Leibovitch S et al. CD44: a new means to inhibit acute myeloid leukemia cell proliferation via p27Kip1. Blood 2004; 103: 1059–1068.

    Article  CAS  Google Scholar 

  3. Harnois T, Constantin B, Rioux A, Grenioux E, Kitzis A, Bourmeyster N . Differential interaction and activation of Rho family GTPase by p210bcr−abl and p190bcr−abl. Oncogene 2003; 22: 6445–6454.

    Article  CAS  Google Scholar 

  4. Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM . p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev 2004; 18: 862–876.

    Article  CAS  Google Scholar 

  5. Mughal T, Cortes J, Cross NC, Donato N, Hantschel O, Jabbour E et al. Chronic myeloid leukemia – some topical issues. Leukemia 2007; E-pub May 10.

  6. Diaz-Blanco E, Bruns I, Neumann F, Fischer JC, Graef T, Rosskopf M et al. Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia 2007; 21: 494–504.

    Article  CAS  Google Scholar 

  7. Jiang Y, Zhao RCH, Verfaillie CM . Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34+ cell proliferation: BCR/ABL upregulates the cyclin-dependent kinase inhibitor, p27Kip1, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity. Proc Natl Acad Sci USA 2000; 97: 10538–10543.

    Article  CAS  Google Scholar 

  8. Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel EM, Waddell MB et al. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 2007; 128: 269–280.

    Article  CAS  Google Scholar 

  9. Cheng T . Cell cycle inhibitors in normal and tumor stem cells. Oncogene 2004; 23: 7256–7266.

    Article  CAS  Google Scholar 

  10. Sengupta A, Banerjee D, Chandra S, Banerji SK, Ghosh R, Roy R et al. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. Leukemia 2007; 21: 949–955.

    Article  CAS  Google Scholar 

  11. Sengupta A, Banerjee D, Chandra S, Banerjee S . Gene therapy for BCR-ABL+ human CML with dual phosphorylation resistant p27kip1 and stable RNA interference using an EBV vector. J Gene Med 2006; 8: 1251–1261.

    Article  CAS  Google Scholar 

  12. Oakley EJ, Van Zant G . Unraveling the complex regulation of stem cells: implications for aging and cancer. Leukemia 2007; 21: 612–621.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Drs Tony Hunter and Joyce Slingerland for providing p27 constructs used in our studies. Grateful acknowledgement is earnestly due to Drs David Scadden, Jon Aster, Tom Kadesch, Hans Clevers, Chris Albanese, Toshiyuki Sakai, Jacqueline Bromberg and John Clifford for various molecular constructs that were used to decipher crosstalk among self-renewal-associated signaling pathways in CML CD34+ cells. This study would not have been possible without their generous cooperation. We also thank Saha Institute of Nuclear Physics for financial assistance and regret for not citing several original references owing to space constraints.

Author information

Authors and Affiliations

  1. Structural Genomics Section and Biophysics Division, Saha Institute of Nuclear Physics, Kolkata, India

    A Sengupta & S Banerjee

Authors
  1. A Sengupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Banerjee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sengupta, A., Banerjee, S. Pleiotropic p27Kip1, BCR-ABL and leukemic stem cell: the trio in concert. Leukemia 21, 2559–2561 (2007). https://doi.org/10.1038/sj.leu.2404842

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404842

This article is cited by

Search

Advanced search

Quick links