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

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

“…We have previously demonstrated that S780 of pRb is more efficiently phosphorylated by cyclin D3-CDK4/6 complexes, whereas cyclin D1 more efficiently drives the phosphorylation at S807/811 and T826. 54 Moreover T821 is a specific target of CDK6 in addition to CDK2. 55 Our results suggested that pretreatment of T98G cells with PD0332991 could somehow increase CDK4/6 activity and that this impact could more selectively target cyclin D3-associated activity.…”

Signal transduction in the human thyrocyte and its perversion in thyroid tumors

“…The fact that c-myc is even repressed by cAMP (after a first very transient induction) also likely prevents its dedifferentiating impact observed in a variety of cell types. The specific involvement of cyclin D3 in the cAMP-dependent mitogenic stimulation of dog and human thyrocytes is also interesting in this context (Depoortere et al, 1998;Paternot et al, 2006a). We have recently shown that the differential use of cyclin D1 or cyclin D3 affects quantitatively and qualitatively the phosphorylation site specificity of the pRb-kinase CDK4, including in dog and human thyrocytes (Fig.…”

“…TSH, unlike all the other known mitogenic factors, does not induce the accumulation of cyclins D, but it paradoxically stimulates the expression of p27 kip1 (Depoortere et al, 1996). However the predominant cyclin D3 is required for the proliferation stimulated by TSH, but not in the proliferation of dog thyrocytes stimulated by EGF or HGF which induce cyclins D1 and D2 (Depoortere et al, 1998;Paternot et al, 2006a). In dog thyrocytes, the formation and the nuclear translocation of essential cyclin D3-CDK4 complexes depend on the synergistic interaction of TSH and insulin.…”

“…Some signaling features, when they lead to selective proliferative advantages, might have been acquired during the establishment and continuous cultures of the cell lines and stabilized by subcloning. On the other hand, both the specific cyclin D3 requirement (Depoortere et al, 1998;Motti et al, 2003;Paternot et al, 2006a) and the cAMP-dependent, rapamycin-sensitive, regulation of CDK4 phosphorylation have been observed in both dog thyrocytes and PC Cl3 cells (Blancquaert et al, submitted).…”

Interweaving the Cell Cycle Machinery with Cell Differentiation

“…The specific composition of cyclin D-cdk4-Kip complexes can change in response to different mitogens. 20 Binding of p21 or p27 to cyclin D-cdk4 complexes in non-quiescent cells does not interfere with its Rb-kinase activity in a significant manner; in fact, Kip-bound cyclin D-cdk4 complexes have greater activity than cyclin D-cdk4 complexes not bound by Kips. 21,22 On the other hand, ternary complex formation (cyclin D-cdk4-Kip) in quiescent cells is inhibitory.…”