Relationship: 1712



Cell cycle, disrupted leads to Apoptosis

Upstream event


Cell cycle, disrupted

Downstream event



Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Histone deacetylase inhibition leading to testicular atrophy adjacent Moderate Moderate

Taxonomic Applicability


Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Oryctolagus cuniculus Oryctolagus cuniculus Moderate NCBI

Sex Applicability


Sex Evidence
Unspecific High

Life Stage Applicability


Term Evidence
Not Otherwise Specified High

Key Event Relationship Description


Cell cycle dysregulation leads to apoptosis. Cell cycles characterized by the DNA content changes regulate cell death and cell proliferation [Lynch, 1986].

Evidence Supporting this KER


microRNA-497, potentially targeting Bcl2 and Cyclin D2 (CCND2), induced apoptosis via the Bcl-2/Bax - caspase 9 - caspase 3 pathway and CCND2 protein in human umbilical vein endothelial cells (HUVECs) [Wu, 2016]. The microRNA-497 activated caspases 9 and 3, and decreased Bcl2 and CCND2 [Wu, 2016]. CCND2 is an important cell cycle gene that induces G1 arrest [Li, 2012], and deregulated CCND2 is implicated in cell proliferation inhibition [Wu, 2016, Mermelstein, 2005, Dong, 2010].

Biological Plausibility


The incidence of apoptosis was increased in vincristine-treated cells, in which metaphases were arrested, compared to untreated cells, which indicates that cell cycle dysregulation leads to apoptosis [Sarraf, 1986]. Cell gain and loss are balanced with mitosis and apoptosis [Cree, 1987]. Apoptosis is mediated by caspase activation [Porter, 1999]. Caspase-3 is activated in the programmed cell death, and the pathways to caspase-3 activation include caspase-9 and mitochondrial cytochrome c release [Porter, 1999]. The activation of caspase-3 leads to apoptotic chromatin condensation and DNA fragmentation [Porter, 1999]. Sinularin, a marine natural compound, exhibited DNA damage and induced G2/M cell cycle arrest, followed by apoptosis in human hepatocellular carcinoma HepG2 cells [Chung, 2017]. Sinularin induced caspases 8, 9, and 3, and pro-apoptotic protein Bax, whereas it decrease the anti-apoptotic Bcl-2 protein expression level [Chung, 2017].


Empirical Evidence


  • Cell cycle arrest such as G1 arrest and G1/S arrest are observed in apoptosis [Li, 2012, Dong, 2010].
  • microRNA-1 and microRNA-206 represses CCND2, while microRNA-29 represses CCND2 and induces G1 arrest and apoptosis in rhabdomyosarcoma [Li, 2012].
  • The blockade of G1/S transition of cell cycle and reduction of CDK4 and CDK2, and apoptosis are occured in HDAC inhibitor treatment [Parajuli, 2014].

Uncertainties and Inconsistencies


MAA induces CDK4 and CDK2 decreases, cell cycle arrest and apoptosis, which may be regulated by several pathways [Parajuli, 2014].

Quantitative Understanding of the Linkage


Cell proliferation which was determined at daily intervals agter a 24-hr pulse of [3H]thymidine changed as the amount of DNA in the cultures changed. Cell death which was measured by lactic dehydrogenase (LDH) activity in the medium changed in parallel with the changes in cell proliferation [Lynch, 1986]. The decrease in total DNA was measured, the increase in cell death was observed [Lynch, 1986].

Response-response Relationship




MAA (5 mM) decreases CDK4, CDK2 expression in 48 hrs after the treatment, which indicates the G1 arrest [Parajuli, 2014]. MAA (5 mM) decreases the protein expression of procaspase 7 and 3 in 24 to 72 hrs after the treatment, indicating the activation of caspases 7 and 3 [Parajuli, 2014].

Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


The relationship between disrupted cell cycle and apoptosis is likely well conserved between species.

  • MicroRNA let-7a induced cell cycle arrest, inhibited CCND2 and proliferation of human prostate cancer cells (Homo sapiens) [Dong, 2010].
  • microRNA-497 down-regulated CCND2 and induced apoptosis via the Bcl-2/Bax-caspase 9- caspase 3 pathway in HUVECs (Homo sapiens) [Wu, 2016].
  • micoRNA-26a regulated p53-mediated apoptosis and CCND2 and CCNE2 in mouse hepatocyte (Mus musculus) [Zhou, 2016].



Lynch MP et al. (1986) Evidence for soluble factors regulating cell death and cell proliferation in primary cultures of rabbit endometrial cells grown on collagen. Proc Natl Acad Sci USA 83: 4784-4788

Wu R et al. (2016) microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs. PLoS One 11: e0167052

Li L et al. (2012) Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma. Lab Invest 92: 571-583

Mermelshtein A et al. (2005) Expression of F-type cyclins in colon cancer and in cell lines from colon carcinomas. Br J Cancer 93: 338-345

Dong Q et al. (2010) microRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS One 5: e10147

Kerr JFR et al. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239-257

Sarraf CE and Bowen ID (1986) Kinetic studies on a murine sarcoma and an analysis of apoptosis. Br J Cancer 54: 989-998

Cree IA et al. (1987) Cell death in granulomata: the role of apoptosis J Clin Pathol 40: 1314-1319

Porter AG and Janicke RU. (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6: 99-104

Chung TW et al. (2017) Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells. BMC Complement Altern Med 17: 62

Parajuli KR et al. (2014) Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. Am J Clin Exp Urol 2:300-313

Zhou J et al. (2016) miR-26a regulates mouse hepatocyte proliferation via directly targeting the 3’ untranslated region of CCND2 and CCNE2. Hepatobiliary Pancreat Dis Int 15: 65-72