Mechanisms underlying maintenance of smooth muscle cell quiescence in rat aorta: role of the cyclin dependent kinases and their inhibitors

Izzard, T; Taylor, Christine; Birkett, Sonia D.; Jackson, Christopher L.; Newby, Andrew C.

doi:10.1016/s0008-6363(01)00444-8

Cited by 33 publications

(37 citation statements)

References 23 publications

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“…20 In addition, balloon injury of the aorta in the same manner as in the carotid artery significantly reduced R-cadherin protein levels by 45%Ϯ6% at 0.25 hours after injury (nϭ4, data not shown). Furthermore, the amount of R-cadherin remained significantly lower by 75%Ϯ16% than in uninjured controls in rings after culture for 24 hours (nϭ4, data not shown).…”

Section: Effect Of Cadherin Perturbation On Vsmc Proliferationmentioning

confidence: 89%

“…20 Rings were incubated for 24 hours at 37°C and 5% CO 2 in media supplemented with 10% fetal calf serum and 1 Ci/mL [ 3 H]-thymidine (Amersham International, Little Chalfont, UK). Cadherin function was inhibited by the addition of 10 g/mL rabbit antihuman R-cadherin antibody (Santa Cruz, Cambridge, UK), 80 g/mL mouse antihuman N-cadherin (Clone A-CAM; Sigma) antibody, or 200 g/mL HAV peptide (Leu-ArgAla-His-Ala-Val-Asp-Val-Asn-Gly-NH 2 ; Bachem, Walden, UK) and compared with the controls (10 g/mL nonimmune rabbit immunoglobulin G (IgG), 80 g/mL nonimmune mouse IgG, or 200 g/mL of the control HGV peptide, respectively).…”

Section: Proliferation Of Vsmcs In Rat Aortic Ringsmentioning

confidence: 99%

“…35,36 To determine whether cadherin regulation was necessary for or merely a consequence of proliferation, we used an organ culture of balloon-injured rat aorta as previously described. 20,37 Inhibition of classical cadherin function by incubation in the presence of a HAV peptide or R-cadherin function with a neutralizing antibody increased VSMC proliferation. This increased proliferation was associated with increased presence of ␤-catenin in nuclei and expression of cyclin D1, supporting our in vivo findings.…”

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confidence: 99%

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R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Slater

Koutsouki

Jackson

et al. 2004

ATVB

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Objective-Vascular smooth muscle cell (VSMC) proliferation is an important component of atherosclerosis, restenosis after angioplasty and stent placement, and vein graft failure. Outside-in signaling from the cadherin:␤-catenin complex can increase transcription of the cell-cycle gene cyclin D1; however, its role in VSMC proliferation has only recently been considered. Methods and Results-We examined the involvement of R-cadherin and ␤-catenin in VSMC proliferation in ballooninjured carotid arteries in vivo and aortic rings in vitro. The number of medial VSMCs positive for R-cadherin was significantly reduced by 32%Ϯ5%, 52%Ϯ10%, and 23%Ϯ2% at 0.25, 24, and 48 hours after injury in vivo, respectively. These changes in cadherin expression coincided with the detection of nuclear ␤-catenin and elevated cyclin D1 expression. Furthermore, loss of R-cadherin expression was associated with medial VSMC proliferation. Inhibition of classical cadherin function with a HAV peptide and R-cadherin neutralizing antibodies significantly increased proliferation by 4.3Ϯ1.0-fold and 4.1Ϯ0.98-fold, and increased the number of cells with ␤-catenin in the nucleus and expressing cyclin D1 in aortic rings. Conclusions-These results suggest that R-cadherin expression and ␤-catenin signaling may be associated with increased cyclin D1 expression and VSMC proliferation and may therefore play an important role in vascular disease. Key Words: smooth muscle Ⅲ cadherin Ⅲ proliferation Ⅲ intimal thickening V ascular smooth muscle cell (VSMC) proliferation plays a key role in pathological processes characterized by neointimal thickening, such as atherosclerosis, vascular rejection, and restenosis after angioplasty and stent placement. 1,2 Balloon injury of arteries causes quiescent, medial cells to lose their differentiated, contractile phenotype and proliferate for up to 3 days. [3][4][5] After this first wave of medial VSMC proliferation, medial VSMCs migrate and appear in the intima 4 days after injury. A new proliferative wave is then observed in the intima, which peaks at Ϸ7 days. Increased synthesis of extracellular matrix components continues for at least 4 weeks after injury. 6 The cadherins are a family of transmembrane glycoproteins that mediate calcium-dependent homophilic cell-cell interaction. 7 One cell type can express multiple cadherins, and the expression pattern is cell type-specific. 8 The extracellular domain of cadherins promotes the cell-cell adhesion through a binding site, which contains a HAV motif in the classical type I cadherins. 9 The cytoplasmic region connects cadherins to the cytoskeletal components through the catenin proteins. In addition to serving a structural function by linking to the actin cytoskeleton, the classical cadherins act as signaling receptors that affect cell behavior, including cell proliferation, migration, and differentiation. 10,11 In the absence of Wnt signals, ␤-catenin is either coupled to cadherins and the cytoskeleton at the plasma membrane or targeted for proteosomal degradation by the a...

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Section: Effect Of Cadherin Perturbation On Vsmc Proliferationmentioning

confidence: 89%

Section: Proliferation Of Vsmcs In Rat Aortic Ringsmentioning

confidence: 99%

mentioning

confidence: 99%

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R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Slater

Koutsouki

Jackson

et al. 2004

ATVB

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“…Smooth muscle cells in mature arteries in rat have low rates of proliferation. Suppression of proliferation is dependent on the upregulated levels of p16 and p27, which makes these cells unable to activate cyclinD1 and cyclinE and their associated kinase activties (Izzard et al, 2002). p16 has also been associated with a variety of additional cell proliferation control proteins that either bind and suppress its function or compete for p16 targets.…”

Section: Role Of P16 In Cell Quiescencementioning

confidence: 99%

“…The levels of p27 and p16 proteins are significantly increased in contact-inhibited human fibroblasts while in contrast, levels were low in serum-deprived human fibroblasts but in both cases, even through the mechanisms of growth arrest are different, they both affect the same pathway involving CDK4, cyclin D1, and Rb (Dietrich et al, 1997). Maintenance of p16 and p27 levels have also been shown to contribute to the low levels of proliferation in normal blood vessels (Izzard et al, 2002) and p16 mRNA and protein accumulate in human fibroblasts as they become senescent (Hara et al, 1996).…”

Section: Role Of P16 In Cell Senescencementioning

confidence: 99%

Tumor Suppressor Gene p16/INK4A/CDKN2A and Its Role in Cell Cycle Exit, Differentiation, and Determination of Cell Fate

Agarwal¹,

Kabir²,

DeInnocentes³

et al. 2012

Tumor Suppressor Genes

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Tumor suppressor gene p16/INK4A/CDKN2A‐dependent regulation into and out of the cell cycle in a spontaneous canine model of breast cancer

Agarwal

Sandey

DeInnocentes

et al. 2013

J of Cellular Biochemistry

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p16/INK4A/CDKN2A is an important tumor suppressor gene that arrests cell cycle in G1 phase inhibiting binding of CDK4/6 with cyclin D1, leaving the Rb tumor suppressor protein unphosphorylated and E2F bound and inactive. We hypothesized that p16 has a role in exit from cell cycle that becomes defective in cancer cells. Well characterized p16-defective canine mammary cancer cell lines (CMT28, CMT27, and CMT12), derived stably p16-transfected CMT cell clones (CMT27A, CMT27H, CMT28A, and CMT28F), and normal canine fibroblasts (NCF), were used to investigate expression of p16 after serum starvation into quiescence followed by re-feeding to induce cell cycle re-entry. The parental CMT cell lines used lack p16 expression either at the mRNA or protein expression levels, while p27 and other p16-associated proteins, including CDK4, CDK6, cyclin D1, and Rb, were expressed. We have successfully demonstrated cell cycle arrest and relatively synchronous cell cycle re-entry in parental CMT12, CMT28 and NCF cells as well as p16 transfected CMT27A, CMT27H, CMT28A, and CMT28F cells and confirmed this by (3)H-thymidine incorporation and flow cytometric analysis of cell cycle phase distribution. p16-transfected CMT27A and CMT27H cells exited cell cycle post-serum-starvation in contrast to parental CMT27 cells. NCF, CMT27A, and CMT28F cells expressed upregulated levels of p27 and p16 mRNA, post-serum starvation, as cells exited cell cycle and entered quiescence. Because quiescence and differentiation are associated with increased levels of p27, our data demonstrating that p16 was upregulated along with p27 during quiescence, suggests a potential role for p16 in maintaining these non-proliferative states.

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Mechanisms underlying maintenance of smooth muscle cell quiescence in rat aorta: role of the cyclin dependent kinases and their inhibitors

Abstract: Cell cycle entry is prevented in aortic tissue, and this is associated with an inability to downregulate p16 and p27 CKIs, and therefore to activate cyclin D1 and cyclin E associated kinase activities.

Cited by 33 publications

References 23 publications

R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

R-Cadherin:β-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Tumor Suppressor Gene p16/INK4A/CDKN2A and Its Role in Cell Cycle Exit, Differentiation, and Determination of Cell Fate

Tumor suppressor gene p16/INK4A/CDKN2A‐dependent regulation into and out of the cell cycle in a spontaneous canine model of breast cancer

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