Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3

Leoni, Vera P.; Ledda-Columbano, Giovanna M.; Pibiri, Monica; Saliba, Christian; Perra, Andrea; Kowalik, Marta Anna; Grober, Olì Maria Victoria; Ravo, Maria; Weisz, Alessandro; Locker, Joseph; Ghiso, Elena; Giordano, Silvia; Columbano, Amedeo

doi:10.1016/j.jhep.2011.02.016

Cited by 8 publications

(7 citation statements)

References 31 publications

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“…No previous studies, to our knowledge, have shown such a remarkable effect on TCPOBOP‐induced proliferative response by altering any mediator other than its direct interacting nuclear receptor, CAR. Several previous studies have suggested that the proliferative response of TCPOBOP was dependent on CAR and not sharing or depending on signaling pathways operative during liver regeneration after PHx . Our current findings in this study change this paradigm.…”

Section: Discussionsupporting

confidence: 64%

“…However, proliferative signaling pathways underlying this CAR‐initiated response are not well characterized. The mechanisms underlying TCPOBOP‐induced direct hyperplasia are considered to be unrelated to classical regenerative pathways, with studies showing no role of cytokines such as IL‐6 and TNF‐α . Recent studies have indicated an emerging role of various signaling mediators in this context such as β‐catenin, Hippo signaling/Yes‐associated protein (YAP), c‐myc, forkhead box protein M1 (FOXM1), and mir‐122 .…”

mentioning

confidence: 99%

“…The mechanisms underlying TCPOBOP-induced direct hyperplasia are considered to be unrelated to classical regenerative pathways, with studies showing no role of cytokines such as IL-6 and TNF-α. (4,(8)(9)(10)(11)(12) Recent studies have indicated an emerging role of various signaling mediators in this context such as β-catenin, Hippo signaling/Yes-associated protein (YAP), c-myc, forkhead box protein M1 (FOXM1), and mir-122. (13)(14)(15)(16)(17) However, the role of RTKs (specifically MET and EGFR) is not yet explored.…”

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confidence: 99%

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TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

et al. 2018

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Section: Discussionsupporting

confidence: 64%

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confidence: 99%

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confidence: 99%

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TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

et al. 2018

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“…It has been shown to cause increased hepatocyte proliferation in rats or mice, which is due to thyroid hormone receptor β (TRβ) 7 . It was also shown that T3’s mitogenic effect does not require c-jun 10 , but induces cyclin D1 11 , which is an important target of β-catenin in liver regeneration 12,13 . We directly assessed the role of β-catenin in T3-mediated hepatocyte proliferation and showed that, indeed, T3-induced hepatocyte proliferation is β-catenin dependent 14 .…”

Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration

Alvarado

Puliga²,

Preziosi³

et al. 2016

gene expr

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Triiodothyronine (T3) induces hepatocyte proliferation in rodents. Recent work has shown molecular mechanism for T3’s mitogenic effect to be through activation of β-catenin signaling. Since systemic side effects of T3 may preclude its clinical use, and hepatocytes mostly express T3 hormone receptor β (TRβ), we investigated if selective TRβ agonists like GC-1 may also have β-catenin-dependent hepatocyte mitogenic effects. Here we studied the effect of GC-1 and T3 in conditional knockouts of various Wnt pathway components. We also assessed any regenerative advantage of T3 or GC-1 when given prior to partial hepatectomy in mice. Mice administered GC-1 showed increased pSer675-β-catenin, cyclin D1, BrdU incorporation, and PCNA. No abnormalities in liver function tests were noted. GC-1-injected liver-specific β-catenin knockouts (β-catenin LKO) showed decreased proliferation when compared to wild-type littermates. To address if Wnt signaling was required for T3- or GC-1-mediated hepatocyte proliferation, we used LRP5-6-LKO, which lacks the two redundant Wnt coreceptors. Surprisingly, decreased hepatocyte proliferation was also evident in LRP5-6-LKO in response to T3 and GC-1, despite increased pSer675-β-catenin. Further, increased levels of active β-catenin (hypophosphorylated at Ser33, Ser37, and Thr41) were evident after T3 and GC-1 treatment. Finally, mice pretreated with T3 or GC-1 for 7 days followed by partial hepatectomy showed a significant increase in hepatocyte proliferation both at the time (T0) and 24 h after surgery. In conclusion, like T3, TRβ-selective agonists induce hepatocyte proliferation through β-catenin activation via both PKA- and Wnt-dependent mechanisms and confer a regenerative advantage following surgical resection. Hence, these agents may be useful regenerative therapies in liver transplantation or other surgical settings.

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“…13 In the liver, T3-induced proliferation lacks many early events thought to be critical in liver regeneration, such as activation of latent transcription factors (AP1, NFjB) or increased expression of immediate-early transcription factors (c-fos, c-myc) and c-jun. 14,15 These differences suggest that the signaling pathways activated by T3 by way of TRs may be different from those activated in liver regeneration. Interestingly, T3 has been shown to induce cyclin-D1 expression.…”

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confidence: 99%

Tri-iodothyronine induces hepatocyte proliferation by protein kinase a-dependent β-catenin activation in rodents

et al. 2014

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Thyroid hormone (T3), like many other ligands of the steroid/thyroid hormone nuclear receptor superfamily is a strong inducer of liver cell proliferation in rats and mice. However, the molecular basis of its mitogenic activity, which is currently unknown, must be elucidated if its use in hepatic regenerative medicine is to be considered. F-344 rats or C57BL/6 mice were fed a diet containing T3 for 2-7 days. In rats, administration of T3 led to an increased cytoplasmic stabilization and nuclear translocation of β-catenin in pericentral hepatocytes with concomitant increase in Cyclin-D1 expression. T3 administration to wild-type (WT) mice resulted in increased hepatocyte proliferation, however no mitogenic response in hepatocytes to T3 was evident in the hepatocyte-specific β-catenin knockout mice (KO). In fact, T3 induced β-catenin-TCF4 reporter activity both in vitro and in vivo. Livers from T3-treated mice demonstrated no changes in Ctnnb1 expression, activity of Glycogen synthase kinase-3β known to phosphorylate and eventually promote β-catenin degradation, or E-cadherin-β-catenin association. However, T3 treatment increased β-catenin phosphorylation at Ser675, an event downstream of protein kinase A (PKA). Administration of PKA inhibitor during T3 treatment of mice and rats as well as in cell culture abrogated Ser675-β-catenin and simultaneously decreased Cyclin-D1 expression to block hepatocyte proliferation. Conclusion We have identified T3-mediated hepatocyte mitogenic response to be mediated by PKA-dependent β-catenin activation. Thus, T3 may be of therapeutic relevance to stimulate β-catenin signaling to in turn induce regeneration in selected cases of hepatic insufficiency.

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Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3

Cited by 8 publications

References 31 publications

TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration

Tri-iodothyronine induces hepatocyte proliferation by protein kinase a-dependent β-catenin activation in rodents

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