The retinoblastoma susceptibility gene product/Sp1 signalling pathway is modulated by Ca2+/calmodulin kinases II and IV activity.
To investigate the possible link between Ca2+ signalling and cell cycle control we analysed Ca2+/calmodulin kinases (CamK) interaction with the retinoblastoma susceptibility gene product/SP1 pathway. CamK II and IV activate c-fos transcription through a short promoter region (-99 to -53) containing the retinoblastoma control element (RCE) and a cAMP response element (CRE) related sequences. Deletion analysis revealed that the RCE is a major CamK responsive element and is sufficient to confer CamK and Ca2+ regulation to a minimal promoter. Direct interactions between SP1 and RCE were confirmed by gel shift experiments. Using transient transfection experiments, we show that CamK-dependent transcription is regulated by the retinoblastoma (Rb) susceptibility gene product and the p107 Rb related protein. However, the stimulatory effects of CamKs and Rb on c-fos are blocked by overexpression of both proteins. These effects appear to be directly mediated by SP1 as shown by the use of a Gal4/SP1 fusion proteins. In conclusion, CamK II and IV, two major Ca2+-dependent intracellular effectors, may represent a molecular link between this second messenger transduction pathway and effectors that control cell cycle progression through Rb/SP1 signalling pathway.
Sohm
F
F
IPCB, UMR 7519 CNRS, Strasbourg, France.
Gaiddon
C
C
Antoine
M
M
Boutillier
A L
AL
Loeffler
J P
JP
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D051379:Mice; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D019572:Retinal Neoplasms / Q000235:genetics*; D012175:Retinoblastoma / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D016760:Proto-Oncogene Proteins c-fos; D016329:Sp1 Transcription Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse