Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli

Ledda-Columbano, Giovanna M.; Pibiri, Monica; Concas, Danilo; Cossu, Costanza; Tripodi, Marco; Columbano, Amedeo

doi:10.1053/jhep.2002.36159

Cited by 43 publications

(46 citation statements)

References 32 publications

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“…Cell proliferation during liver regeneration in response to CCl 4 induced liver injury was normal in GCIP transgenic mice compared with the wild-type mice. Although GCIP may affect E2F-1 and cyclinD1 activities in our in vitro assays, data obtained from the GCIP transgenic mice are similar to the overexpression of E2F-1 and cyclin D1 in mice liver (Conner et al, 2000;Ledda-Columbano et al, 2002), in which no obvious changes was observed in hepatic regenerative growth and proliferation after partial hepatectomy (Conner et al, 2000) and mitogenic stimuli (LeddaColumbano et al, 2002), respectively.…”

Section: Discussionsupporting

confidence: 58%

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

Xia

Stafford

et al. 2006

Oncogene

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Transcription factors with helix-loop-helix (HLH) motif play critical roles in controlling the expression of genes involved in lineage commitment, cell fate determination, proliferation, and tumorigenesis. To examine whether the newly identified HLH protein GCIP/CCNDBP1 modulates cell fate determination and plays a role in hepatocyte growth, proliferation, and hepatocarcinogenesis, we generated transgenic mice with human GCIP gene driven by a liver-specific albumin promoter. We demonstrated that in GCIP transgenic mice, the overall liver growth and regeneration occurred normally after liver injury induced by carbon tetrachloride (CCl 4 ). In the diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis, we demonstrated that overexpression of GCIP in mouse liver suppressed DEN-induced hepatocarcinogenesis at an early stage of tumor development. The number of hepatic adenomas at 24 weeks was significantly lower or not detected in GCIP transgenic male mice compared to the control mice under the same treatment. Although GCIP has little inhibition on the number of hepatic tumors at later stages (40 weeks), hepatocellular tumors in GCIP transgenic mice are smaller and well-differentiated compared to the poorly differentiated tumors in wildtype mice. Furthermore, we demonstrate that GCIP functions as a transcriptional suppressor, regulates the expression of cyclin D1, and inhibits anchorage-independent cell growth and colony formation in HepG2 cells, suggesting a significant role of GCIP in tumor initiation and development.

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Section: Discussionsupporting

confidence: 58%

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

Xia

Stafford

et al. 2006

Oncogene

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“…15 However, in knockout mice, lack of cyclin D1 might transiently delay entry into S phase but was not sufficient to inhibit the response of hepatocytes to mitogenic stimuli. 35 Under our experimental conditions, overexpression of cyclin D1 could never allow non-growth factor-stimulated rat hepatocytes to progress in S phase, indicating that G 1 arrest was not strictly attributable to the loss of cyclin D1 alone (results not shown).…”

Section: Discussionmentioning

confidence: 65%

ERK2 but not ERK1 plays a key role in hepatocyte replication

et al. 2007

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The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 have been implicated in various physiological events, and specific targeting of these MAPKs could affect cell proliferation in many cell types. First, to evaluate the potential specific roles of these two MAPKs, we analyzed the mitogenic response in regenerating liver after partial hepatectomy (PH) and in primary culture of hepatocytes isolated from ERK1-deficient mice. We show that ERK1 knockout and wild-type (wt) cells replicate with the same kinetics after PH in liver, in vivo, and in primary cultures of hepatocytes, in vitro. Indeed, Cyclin D1 and Cdk1 appear to be expressed concomitantly in knockout and wt cells, highlighting that hepatocytes progress in the cell cycle independently of the presence of ERK1. Second, we specifically abolished ERK2 expression by RNA interference in mouse and rat hepatocytes. We investigated whether small interfering RNA (siRNA) targeting ERK2 could specifically inhibit its expression and interfere with the process of replication. In ERK1-deficient hepatocytes, silencing ERK2 expression by RNA interference and ERK2 activation by U0126 clearly demonstrate that DNA replication is regulated by an ERK2-dependent mechanism. Furthermore, in rat wt hepatocytes, whereas ERK2 targeting inhibits late G 1 and S phase progression, ERK1 silencing is devoid of any effect on cell proliferation, indicating that ERK1 cannot rescue ERK2 deficiency. Conclusion: Our results emphasize the importance of the MAPK cascade in hepatocyte replication and allow us to conclude that ERK2 is the key form involved in this regulation, in vivo and in vitro. T he Ras-dependent mitogen-activated protein kinase (MAPK) signaling cascade participates in control of cell fate, proliferation, and survival in various mammalian organs, including the liver. In adult rodent hepatocytes and regenerating liver, the MAPK MEK/ERK cascade plays a key role in regulating G 1 phase progression and consequently proliferation. 1,2 The ability to control precisely the order and timing of events is determinant for cell cycle regulation. 3,4 According to our previous data, the first part of G 1 is devoted to growth factor-dependent MEK/ERK-morphogenic events, whereas the mitogenic signal occurs in mid-G 1 phase. We showed that the sequential control mechanism of hepatocyte morphology and S phase entry by growth factor could involve successive activation of MEK2-ERK2 and then MEK1/MEK2-ERK1/ERK2 isoforms. 3 The process in early G 1 in relation to cytoskeletal reorganization induces hepatocyte spreading, making them permissive to DNA replication. In late G 1 phase, MEK1/MEK2-ERK1/ERK2 activation is associated with accumulation of Cyclin D1 and mitogen-dependent progression of hepatocytes to S phase. The central role of ERK2 in regulation was highlighted by the observation that ERK2 was preferentially activated in early and midlate G 1 phase. However, although ERK1 was slightly expressed and phosphorylated in early G 1 , a gradual

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“…First, the reduction of Ccnd1 mRNA and protein levels is already observed in resting conditions, suggesting a direct target of S6K1 activity and not a consequence of the delay in cell cycle progression (Figure 7). Second, cyclin D1 is known to promote hepatocyte cell cycle progression, as demonstrated by ectopic overexpression and genetic invalidation experiments (24,35). Importantly, cyclin D1 overexpression rescues the inhibitory effect of S6K deletion on S phase entry after PH (Figure 8), providing a causal link among mTOR/S6K pathway, cyclin D1 expression, and cell cycle progression.…”

Section: Discussionmentioning

confidence: 88%

S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy

et al. 2011

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Rapamycin is an antibiotic inhibiting eukaryotic cell growth and proliferation by acting on target of rapamycin (TOR) kinase. Mammalian TOR (mTOR) is thought to work through 2 independent complexes to regulate cell size and cell replication, and these 2 complexes show differential sensitivity to rapamycin. Here we combine functional genetics and pharmacological treatments to analyze rapamycin-sensitive mTOR substrates that are involved in cell proliferation and tissue regeneration after partial hepatectomy in mice. After hepatectomy, hepatocytes proliferated rapidly, correlating with increased S6 kinase phosphorylation, while treatment with rapamycin derivatives impaired regeneration and blocked S6 kinase activation. In addition, genetic deletion of S6 kinase 1 (S6K1) caused a delay in S phase entry in hepatocytes after hepatectomy. The proliferative defect of S6K1-deficient hepatocytes was cell autonomous, as it was also observed in primary cultures and hepatic overexpression of S6K1-rescued proliferation. We found that S6K1 controlled steady-state levels of cyclin D1 (Ccnd1) mRNA in liver, and cyclin D1 expression was required to promote hepatocyte cell cycle. Notably, in vivo overexpression of cyclin D1 was sufficient to restore the proliferative capacity of S6K-null livers. The identification of an S6K1-dependent mechanism participating in cell proliferation in vivo may be relevant for cancer cells displaying high mTOR complex 1 activity and cyclin D1 accumulation.

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Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli

Cited by 43 publications

References 32 publications

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis

ERK2 but not ERK1 plays a key role in hepatocyte replication

S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy

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