Control of cell proliferation, Cancer
Our group has pioneered the study of thyroid cell proliferation and differentiation, and has demonstrated in these cells the existence of three cascades of mitogenic signal transduction, TSH/adenylyl cyclase/cAMP, EGF-HGF/ras/MAPK and phorbol esters/phospholipase C/protein kinase C. The cAMP pathway promotes both proliferation and differentiation within thyrocytes and is causatively involved in goitrogenesis, tumor promotion and generation of hyperfunctional adenomas. The positive regulation of thyroid cell cycle by cAMP is unique as it targets the assembly and activation of complexes of pre-existing cyclin D and CDK4 without involving most of the intermediaries of known mitogenic signaling cascades. Ongoing studies include the identification by molecular biology techniques (PCR-derived methods, microarrays…) of new genes regulated by cAMP and the investigation by proteomic approaches and two-hybrids methology of the novel mechanisms of CDK4 activation by cAMP. Extension of this work to thyroid tumors involves the analysis of gene expression profiles in those tissues by the microarray technology.
Heimann P, El Housni H, Ogur G, Weterman MA, Petty EM, Vassart G.
Fusion of a novel gene, RCC17, to the TFE3 gene in t(X ;17)(p&&.2 ;q25.3)-bearing
papillary renal cell carcinomas
Cancer Res.61 :4130-4135 (2001).
Coulonval K, Bockstaele L, Paternot S, Dumont JE, Roger PP.
The cyclin D3-CDK4-p27kip1 holoenzyme in thyroid epithelial cells: activation
by TSH, inhibition by TGFbeta, and phosphorylations of its subunits demonstrated
by two-dimensional gel electrophoresis.
Exp Cell Res. 291(1):135-49 (2003).
Detours V., Wattel S., Venet D., Hutsebaut N., Bogdanova T., Tronko M., Dumont J.E., Franc B., Thomas G., Maenhaut C.
Absence of a specific radiation signature in post-Chernobyl thyroid cancers.
Br. J. Cancer 92: 1545-1552 (2005).
Wattel S., Mircescu H., Venet, D., Burniat A., Franc, B., Andry, G., Van Sande J., Rocmans P., Detours V., Dumont J.E., Maenhaut C.
Gene expression in thyroid autonomous adenoma provides insight on their pathology.
Oncogene 24: 6902-6916 (2005).
Fortemaison N, Blancquaert S, Dumont JE, Maenhaut C, Aktories K, Roger PP, Dremier S.
Differential involvement of the actin cytoskeleton in differentiation and mitogenesis of thyroid cells:
inactivation of Rho proteins contributes to cyclic adenosine monophosphate-dependent
gene expression but prevents mitogenesis.
Endocrinology. 146(12):5485-95 (2005)
van Staveren W., Weiss D., Delys, L., Venet D., Cappello M., Andry G., Dumont J.E., Libert F., Detours V., Maenhaut C.
Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis.
Proc. Natl. Acad. Sci, 103, 413-418 (2006).
van Staveren W., Detours V., Dumont J.E., Maenhaut C.
Negative feedbacks in normal cell growth and their suppression in tumorigenesis.
Cell Cycle 5, 571-572 (2006).
Paternot S, Arsenijevic T, Coulonval K, Bockstaele L, Dumont JE, Roger PP.
Distinct specificities of pRb phosphorylation by CDK4 activated by cyclin D1 or cyclin D3:
differential involvement in the distinct mitogenic modes of thyroid epithelial cells.
Cell Cycle. 5(1):61-70 (2006).