The role of cyclin D2 and p21/waf1 in human T-cell leukemia virus type 1 infected cells

Retrovirology. 2004 Apr 13;1:6. doi: 10.1186/1742-4690-1-6.


Background: The human T-cell leukemia virus type 1 (HTLV-1) Tax protein indirectly influences transcriptional activation, signal transduction, cell cycle control, and apoptosis. The function of Tax primarily relies on protein-protein interactions. We have previously shown that Tax upregulates the cell cycle checkpoint proteins p21/waf1 and cyclin D2. Here we describe the consequences of upregulating these G1/S checkpoint regulators in HTLV-1 infected cells.

Results: To further decipher any physical and functional interactions between cyclin D2 and p21/waf1, we used a series of biochemical assays from HTLV-1 infected and uninfected cells. Immunoprecipitations from HTLV-1 infected cells showed p21/waf1 in a stable complex with cyclin D2/cdk4. This complex is active as it phosphorylates the Rb protein in kinase assays. Confocal fluorescent microscopy indicated that p21/waf1 and cyclin D2 colocalize in HTLV-1 infected, but not in uninfected cells. Furthermore, in vitro kinase assays using purified proteins demonstrated that the addition of p21/waf1 to cyclin D2/cdk4 increased the kinase activity of cdk4.

Conclusion: These data suggest that the p21/cyclin D2/cdk4 complex is not an inhibitory complex and that p21/waf1 could potentially function as an assembly factor for the cyclin D2/cdk4 complex in HTLV-1 infected cells. A by-product of this assembly with cyclin D2/cdk4 is the sequestration of p21/waf1 away from the cyclin E/cdk2 complex, allowing this active cyclin-cdk complex to phosphorylate Rb pocket proteins efficiently and push cells through the G1/S checkpoint. These two distinct functional and physical activities of p21/waf1 suggest that RNA tumor viruses manipulate the G1/S checkpoint by deregulating cyclin and cdk complexes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Line
  • Cells, Cultured
  • Chromatin / genetics
  • Cyclin D2
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology*
  • Cyclins / genetics
  • Cyclins / physiology*
  • Fibroblasts
  • Gene Products, tax / physiology
  • Human T-lymphotropic virus 1 / genetics
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • Mice
  • Microscopy, Confocal
  • Transcriptional Activation


  • CCND2 protein, human
  • CDKN1A protein, human
  • Chromatin
  • Cyclin D2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Gene Products, tax