Disease relevance of CRTC1

• Thus, both TORC and p300 families of coactivators are essential for optimal activation of HTLV-1 transcription by Tax [1].
• Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)--associated TORC1-MAML2 gene fusion [2].
• As a result, both physiologic and pathologic tissue hypertrophy are associated with TORC1 activation [3].
• TORCs, and kinases affecting TORC function, are promising new therapeutic targets for the treatment of diabetes mellitus [4].
• Mucoepidermoid carcinoma of the thyroid (MECT) has been recently recognized as a pathological entity [5].

Psychiatry related information on CRTC1

• CONCLUSION: ECT and MECT combined with flupenthixol were effective in improving psychopathology in patients refractory to antipsychotic medication alone [6].
• The case of a patient with bipolar disorder is presented to illustrate that past clinical course may suggest flexible scheduling strategies for maintenance ECT (MECT), which will allow some patients to be successfully treated with the fewest number of ECT [7].
• Parkinson's disease (PD), schizophrenia, and obsessive-compulsive disorder (OCD), as well as affective disorders coexisting with dementia, neurological disorder, or mental retardation, have also been reported to respond to C/MECT [8].

High impact information on CRTC1

• Our findings reveal that the SIN1-rictor-mTOR function in Akt-Ser473 phosphorylation is required for TORC2 function in cell survival but is dispensable for TORC1 function [9].
• The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders [10].
• MECT1-MAML2 induced foci formation in RK3E epithelial cells, confirming a biological effect for the fusion product [11].
• Loss of tumor suppressors TSC1 or TSC2 leads to aberrant activation of TORC1, which has been implicated in the control of cell size [3].
• The transforming activity of MECT1-MAML2 was markedly reduced by blocking CREB DNA binding [12].

Biological context of CRTC1

• TORC1 potently induced known CREB1 target genes, bound CREB1, and activated expression through a potent transcription activation domain [13].
• TORC1 and TORC2 coactivators are required for tax activation of the human T-cell leukemia virus type 1 long terminal repeats [1].
• Malignant salivary gland tumors can arise from a t(11;19) translocation that fuses 42 residues from Mect1/Torc1, a cyclic AMP (cAMP)/cAMP-responsive element binding protein (CREB)-dependent transcriptional coactivator, with 982 residues from Maml2, a NOTCH receptor coactivator [14].
• The fusion, which results from a t(11;19)(q21-22;p13) translocation, creates a chimeric gene in which exon 1 of a novel gene of unknown function, designated WAMTP1, is linked to exons 2-5 of the recently identified Mastermind-like Notch coactivator MAML2 [15].
• TORC1, which is sensitive to rapamycin, regulates translation and cell growth, whereas TORC2, which is insensitive to rapamycin, regulates cell morphology and cell growth [16].

Anatomical context of CRTC1

• Recent studies in eukaryotic cells have identified two distinct TOR complexes, TORC1 and TORC2, which phosphorylate different substrates and have distinct physiological functions [17].
• In addition, the RNAi-specific vector had no effect on colony growth of non-MEC tumors including a lung tumor or two other salivary gland cell lines that do not express Mect1-Maml2 [18].
• The origin of MECT is unknown but the morphology of this tumour closely resembles features seen in the ultimobranchial body (UB) vestiges [5].

Associations of CRTC1 with chemical compounds

• Biochemical and genetic analyses of these mutant forms of Tor1p support a model wherein functional interactions between the FRB and kinase domains, as well as between the FRB domain and the TORC1 component Kog1p, regulate TOR activity as well as contribute to the mechanism of caffeine resistance [19].
• TOR signals through two physically distinct multiprotein complexes, and the control of cell growth is mediated primarily by TOR complex 1 (TORC1), which contains the polypeptides raptor and LST8 [20].

Enzymatic interactions of CRTC1

• These two opposing signals are connected by the fact that SIK phosphorylates TORC and induces its nuclear export [21].

Other interactions of CRTC1

• A protein, termed transducer of regulated cAMP response element-binding protein (CREB) (TORC1), was identified that activated expression through the variant CRE and consensus CRE sites [13].
• TORC coactivation requires CREB, but not ATF4 or other bZIP factors [1].
• The other two members of the TORC family, TORC2 and TORC3, also strongly activated PGC-1alpha transcription [22].
• Amino-acid depletion inhibits TORC1 acting predominantly downstream of the TSC complex, by interfering with the ability of Rheb to bind to mTOR [20].
• The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility [23].

Analytical, diagnostic and therapeutic context of CRTC1

• The patient had no significant affective episodes or hospitalizations during the 3 years of MECT [7].
• In an attempt to clarify the putative relationship between MECT and PTC, we analysed tissue from 11 patients with MECT by immunohistochemistry (E-, P- and N-cadherins and alpha-, beta- and gamma-catenins) [24].
• Further research is needed, however, to clarify the optimum use of MECT schedules and pharmacotherapy combinations to most effectively and safely prevent relapse of depression in different elderly populations and to help predict who will best respond to which treatment modalities [25].

References