The Kto-Skd Complex Can Regulate ptc Expression by Interacting with Cubitus interruptus (Ci) in the Hedgehog Signaling Pathway

Mao, Feifei; Yang, Xiaofeng; Fu, Lin; Lv, Xiangdong; Zhang, Zhao; Wu, Wenqing; Yang, Siqi; Zhou, Zhaocai; Zhang, Lei; Zhao, Yun

doi:10.1074/jbc.m114.560995

Cited by 7 publications

(4 citation statements)

References 56 publications

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“…The Hh signal response primarily relies on the control of membrane proteins Ptc and Smo [ 13 , 14 ]. The study showed that the expression of both proteins can be significantly inhibited by TMP in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine Inhibits Activation of Hepatic Stellate Cells through Hedgehog Signaling Pathways In Vitro

Cao

et al. 2015

BioMed Research International

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Background and Aim. Tetramethylpyrazine (TMP), a major alkaloid isolated from Ligusticum chuanxiong, has been reported in hepatic fibrosis models. However, the action mechanism remains unclear. In the present study, effects of tetramethylpyrazine (TMP) against hepatic stellate cell (HSC) activation as well as the possible mechanisms were evaluated. Methods. Western blot assay was used to detect TMP effects on protein expression of Smo, Patched, Hhip, and Gli and to investigate the effects of TMP on Cyclin D1, Cyclin E1, CDK2, Bcl-2, Bax, and caspase expression with cyclopamine supplementation. Results. Our results showed that TMP significantly inhibits the expression of Cyclin D1, Cyclin E1, and Cyclin-dependent kinase CDK2 and changes the HSC cycle by inhibiting the proliferation of HSC. Moreover, TMP has also been shown to decrease the expression of Bcl-2 and increase the expression of Bax in HSC-T6 cells. Furthermore, TMP can inhibit the expression of connective tissue growth factor (CTGF), and the inhibitory effect was intensified after the application of joint treatment with TMP and cyclopamine. Conclusion. TMP may be an effective Hh signaling pathway inhibitor for hepatic fibrosis treatment.

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Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine Inhibits Activation of Hepatic Stellate Cells through Hedgehog Signaling Pathways In Vitro

Cao

et al. 2015

BioMed Research International

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“…UAS‐dicer2 was used to increase RNAi efficiency (Flybase). apterous (AP)‐Gal4 , ci‐Gal4 , dpp‐LacZ , ptc‐LacZ , UAS‐HA‐Ci , UAS‐HA‐Rdx , UAS‐Flag‐Slimb, and Slimb RNAi have been described previously . UbcD1 RNAi (NIG 7425R‐1, VDRC 26011), Rdx RNAi (NIG 9924R‐1), UbcD1 mer1 (BS 4656), and FRT82‐UbcD1 s1782 (Kyoto DGGR 111415) were obtained from the National Institute of Genetics, Vienna Drosophila RNAi Center, Bloomington Drosophila Stock Center, or Kyoto Stock Center.…”

Section: Methodsmentioning

confidence: 99%

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

Pan

Xia

et al. 2017

EMBO Reports

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The Hh pathway controls many morphogenetic processes in metazoans and plays important roles in numerous pathologies and in cancer. Hh signaling is mediated by the activity of the Gli/Ci family of transcription factors. Several studies in have shown that ubiquitination by the ubiquitin E3 ligases Slimb and Rdx(Hib) plays a crucial role in controlling Ci stability dependent on the levels of Hh signals. If Hh levels are low, Slimb adds K11- and K48-linked poly-ubiquitin chains on Ci resulting in partial degradation. Ubiquitin E2 enzymes are pivotal in determining the topologies of ubiquitin chains. However, which E2 enzymes participate in the selective ubiquitination-degradation of Ci remains elusive. Here, we find that the E2 enzyme UbcD1 negatively regulates Hh signaling activity in wing disks. Genetic and biochemical analyses in wing disks and in cultured cells reveal that UbcD1 directly controls Ci stability. Interestingly, UbcD1 is found to be selectively involved in Slimb-mediated Ci degradation. Finally, we show that the homologs of UbcD1 play a conserved role in modulating Hh signaling in vertebrates.

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“…The interaction between Ci and Kto‐Skd is greatly enhanced by Hh treatment, which further inhibits the expression of ptc (Mao et al . ).…”

Section: Other Negative Regulations For Hh Activitymentioning

confidence: 97%

Decoding Ci: From partial degradation to inhibition

Liu

Zhao

2014

Dev Growth Differ

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Hedgehog is a morphogen, which is widely involved in the regulation of cell proliferation, differentiation and tissue patterning during development in both vertebrate and invertebrate, such as in coordination of eye, brain, gonad, gut and tracheal development. In invertebrate, Cubitus interruptus (Ci) modification process is the last identified step before transcriptional activation in the Hh signaling pathway. Ci can form a truncated repressor (Ci R /Ci75) or act as an activator (Ci A /Ci155) based on Hh gradient to regulate the expressions of target genes. The activity of Ci is mediated by different mechanisms, including processing, trafficking and degradation. While in vertebrate, Glioblastomas (Glis), homologs of Ci, play similar but more complex roles in the regulation of mammals Hh pathway. Hh signaling is responsible for a wide variety of processes during embryonic development and adult tissue homeostasis. Malfunction of Hh signaling could cause various diseases including birth defects and cancers. Enormous efforts were made in the past decades to explore the Hh pathway regulation and the results have provided us important insights into disease diagnosis and therapeutic treatment. In this review, we focus on a small branch of Hh pathway regulation based on studies in the Drosophila system, mainly about Ci degradation, aiming to explain how Ci is modified by different ubiquitin ligases due to the strong or moderate Hh signals and then been subjected to complete or partial degradation by proteasomes. Overall, we intend to offer an overview on how Ci responds to and relays Hh signals in a precise manner to control target genes expressions and ensures proper Hh signal transduction.

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The Kto-Skd Complex Can Regulate ptc Expression by Interacting with Cubitus interruptus (Ci) in the Hedgehog Signaling Pathway

Cited by 7 publications

References 56 publications

Tetramethylpyrazine Inhibits Activation of Hepatic Stellate Cells through Hedgehog Signaling Pathways In Vitro

Tetramethylpyrazine Inhibits Activation of Hepatic Stellate Cells through Hedgehog Signaling Pathways In Vitro

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

Decoding Ci: From partial degradation to inhibition

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