Molecule Information

General Information of the Molecule (ID: Mol04415)

• Name: CREB-regulated transcription coactivator 1 (CRTC1) ,Homo sapiens
• Synonyms: Mucoepidermoid carcinoma translocated protein 1; Transducer of regulated cAMP response element-binding protein 1
• Molecule Type: Protein
• Gene Name: CRTC1
• Gene ID: 23373
• Sequence:
  MATSNNPRKFSEKIALHNQKQAEETAAFEEVMKDLSLTRAARLQLQKSQYLQLGPSRGQY
  YGGSLPNVNQIGSGTMDLPFQTPFQSSGLDTSRTTRHHGLVDRVYRERGRLGSPHRRPL
  S VDKHGRQADSCPYGTMYLSPPADTSWRRTNSDSALHQSTMTPTQPESFSSGSQDVHQK
  RV LLLTVPGMEETTSEADKNLSKQAWDTKKTGSRPKSCEVPGINIFPSADQENTTALIP
  ATH NTGGSLPDLTNIHFPSPLPTPLDPEEPTFPALSSSSSTGNLAANLTHLGIGGAGQG
  MSTP GSSPQHRPAGVSPLSLSTEARRQQASPTLSPLSPITQAVAMDALSLEQQLPYAFF
  TQAGS QQPPPQPQPPPPPPPASQQPPPPPPPQAPVRLPPGGPLLPSASLTRGPQPPPLA
  VTVPSS LPQSPPENPGQPSMGIDIASAPALQQYRTSAGSPANQSPTSPVSNQGFSPGSS
  PQHTSTL GSVFGDAYYEQQMAARQANALSHQLEQFNMMENAISSSSLYSPGSTLNYSQA
  AMMGLTGS HGSLPDSQQLGYASHSGIPNIILTVTGESPPSLSKELTSSLAGVGDVSFDS
  DSQFPLDEL KIDPLTLDGLHMLNDPDMVLADPATEDTFRMDRL
• Function: Transcriptional coactivator for CREB1 which activatestranscription through both consensus and variant cAMP response element sites. Acts as a coactivator, in the SIK/TORC signaling pathway,being active when dephosphorylated and acts independently of CREB1'Ser-133' phosphorylation. Enhances the interaction of CREB1 with TAF4.Regulates the expression of specific CREB-activated genes such as thesteroidogenic gene, StAR. Potent coactivator of PGC1alpha and inducerof mitochondrial biogenesis in muscle cells. In the hippocampus,involved in late-phase long-term potentiation maintenance atthe Schaffer collateral-CA1 synapses. May be required for dendriticgrowth of developing cortical neurons . In concert withSIK1, regulates the light-induced entrainment of the circadian clock.In response to light stimulus, coactivates the CREB-mediatedtranscription of PER1 which plays an important role in the photicentrainment of the circadian clock. {ECO:0000250|UniProtKB:Q157S1,ECO:0000250|UniProtKB:Q68ED7, ECO:0000269|PubMed:23699513}.; Plays a role of coactivator for TAXactivation of the human T-cell leukemia virus type 1 longterminal repeats . {ECO:0000269|PubMed:16809310}.
• Uniprot ID: CRTC1_HUMAN
• Ensembl ID: ENSG0000010566216
• HGNC ID: HGNC:16062

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma [ICD-11: 2A00.02] [1]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Trametinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: TORC1 signaling pathway; Regulation; N.A.
• In Vitro Model: BT-40 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: NCH-MN-1 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: IC-3635 cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: C.B.17SC scid?/? mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Clonogenic assay; Cellular viability assay; In vivo tumor growth inhibition assay; Orthotopic xenograft assay
• Mechanism Description: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance.

References

• Ref 1: Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models. Clin Cancer Res. 2022 Sep 1;28(17):3836-3849.