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CDKN1A stabilizes Cyclin D3 by inhibiting its phosphorylation-dependent nuclear export following butyrate treatment

ABSTRACT: Butyrate-mediated inhibition of cell proliferation is part of the preventive role of dietary fiber against colorectal cancer (CRC). This effect notably involves the cyclin-dependent kinase inhibitor CDKN1A in human intestinal cells, yet the underlying molecular mechanisms remain incompletely understood. Previously, we observed a paradoxical increase in cyclin D3 (CCND3)—but not cyclin D1—levels upon butyrate exposure. Here, we demonstrate that the butyrate-induced accumulation of CCND3 results primarily from a CDKN1A-dependent stabilization, specifically extending its nuclear half-life. Proteomic analyses of CCND3 co-immunoprecipitates identified complexes involving CDKN1A, CDK4, CDK6, and the CRC-associated kinase CDK5, particularly enriched in butyrate-treated cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Carine Rodrigues

LAB HEAD: Carine Machado Rodrigues

PROVIDER: PXD062450 | Pride | 2026-02-12

REPOSITORIES: pride

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			Action	DRS
	7-23-2023_Ctrl_3_1_5750.d.zip	Other
	7-23-2023_Ctrl_3_1_5750.xml	Xml
	7-23-2023_L3moins_2_1_5744.d.zip	Other
	7-23-2023_L3moins_2_1_5744.xml	Xml
	7-23-2023_L3moins_3_1_5754.d.zip	Other

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Project description:Oxidants induce cell cycle arrest to halt cell proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 and investigate its role in cell proliferation and PH. Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells (HPASMCs) and human pulmonary arterial endothelial cells (HPAECs). Cysteine to alanine mutants were generated, and cell cycle experiments were employed to characterize the nature of this reversible intermolecular disulfide bond. The functional role of the disulfide was delineated using in vitro kinase activity assays, HPASMCs and knock-in cells. Finally, the cyclin D-CDK4 disulfide was assessed in vivo in the pulmonary arteries and isolated HPASMCs of PAH patients, and in three preclinical models of PH. Cyclin D-CDK4 forms an oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively. This reversible modification forms in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity and decrease retinoblastoma protein (Rb) phosphorylation. Correspondingly, treatment of HPASMCs with H2O2 or auranofin induces cell cycle arrest. Notably, mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases the proliferation rate of cells, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and HPASMCs from patients with pulmonary arterial hypertension (PAH) display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in PAH. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental models of PH, by mitigating pulmonary vascular remodeling. A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for design of a selective covalent inhibitor that may prove beneficial in pulmonary hypertension

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CDKN1A stabilizes Cyclin D3 by inhibiting its phosphorylation-dependent nuclear export following butyrate treatment

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