Download Gene Section CRTC2 (CREB regulated transcription coactivator 2) in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
CRTC2 (CREB regulated transcription coactivator 2)
Kristy A Brown, Nirukshi Samarageewa
Prince Henry's Institute, Clayton, Victoria, 3168, Australia (KAB, NS)
Published in Atlas Database: February 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/CRTC2ID50581ch1q21.html
DOI: 10.4267/2042/44907
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
localisation sequence (NLS) at amino acids 56-144 as
well as two nuclear export sequences (NES1 and
NES2) within the region of amino acids 145-320.
Identity
Other names: TORC2, RP11-422P24.6
HGNC (Hugo): CRTC2
Location: 1q21.3
Function
Transcriptional coactivator for CREB (cAMPresponsive element binding protein).The highly
conserved N-terminal coiled-coil domain of the CRTC2
interacts with the bZip domain of CREB which
activates both consensus and variant cAMP response
element (CRE) sites, leading to activation of CREB
target gene expression. CRTC2 responds to stimulation
by cAMP, calcium, fasting hormones, G proteincoupled receptors, and AMPK/SIKs.
DNA/RNA
Description
10,893 bases; on minus strand.
Includes 14 exons.
Transcription
Transcript measures 2598 bp with a 2082 bp coding
sequence.
Implicated in
Protein
Peutz-Jeghers syndrome
Description
Note
Peutz-Jeghers syndrome (PJS) is an autosomaldominant genetic disorder that is characterised by an
increased risk of developing malignant tumours. Most
of the identified mutations in the LKB1 gene are
localised to the catalytic kinase domain so that it is
thought that PJS results from loss of LKB1 kinase
activity. The silencing of LKB1, leads to the decreased
activity of AMPK and SIK and leads to the increased
nuclear translocation and activity of CRTC2.
Disease
Gastrointestinal polyps and cancers including
esophagus, stomach, small intestine, colon, pancreas,
lung, testes, breast, uterus, ovary and cervix.
693 amino acids; 73,302 Da.
Expression
Particularly abundant in B and T lymphocytes. Higher
levels were also seen in muscle, lung, spleen, ovary and
breast. Lower expressions found in brain, colon, heart,
kidney, prostate, small intestine and stomach, with
significantly lowest expression in liver and pancreas.
Localisation
Phosphorylation
of
CRTC2
triggers
the
phosphorylation-dependent binding to 14-3-3 proteins,
and hence sequestration of CRTC2 in the cytosol
thereby preventing its nuclear translocation and the
activation of CREB. Proteins known to phosphorylate
CRTC2 at Ser171 include AMP-
Oestrogen-receptor (ER) positive breast
cancer
Note
The increased prevalence of oestrogen-dependent,
postmenopausal breast cancers is correlated with
activated protein kinase (AMPK) and the salt-inducible
kinases (SIKs). Dephosphorylated CRTC2 readily
translocates to the nucleus. CRTC2 contains a nuclear
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
1104
CRTC2 (CREB regulated transcription coactivator 2)
Brown KA, Samarageewa N
Okamoto M, Montminy M. The CREB coactivator TORC2
functions as a calcium- and cAMP-sensitive coincidence
detector. Cell. 2004 Oct 1;119(1):61-74
elevated local levels of oestrogens as a result of an
increase in cytochrome P450 aromatase expression
within the adipose stromal (hAS) cells surrounding the
breast tumour - aromatase is the enzyme responsible for
the conversion of androgens to oestrogens. This is
governed by promoter switching from the distal
promoter I.4 to the proximal promoter PII on the
CYP19A1 gene, that encodes aromatase, in response to
factors derived from the tumour such as prostaglandin
E2 (PGE2). Interestingly, the LKB1/ AMPK pathway
has been shown to inhibit aromatase expression via the
cytoplasmic sequestration of CRTC2. However, PGE2
inhibits LKB1/AMPK signaling, leading to the nuclear
translocation of CRTC2 and its enhanced binding and
activation of aromatase promoter PII in hAS cells.
Furthermore, the adipokine leptin, produced at higher
levels in obesity, has been shown to cause an increase
in CRTC2 nuclear translocation and consequently, in
aromatase expression.
Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent
signaling pathways. Annu Rev Biochem. 2006;75:137-63
Katoh Y, Takemori H, Lin XZ, Tamura M, Muraoka M, Satoh T,
Tsuchiya Y, Min L, Doi J, Miyauchi A, Witters LA, Nakamura H,
Okamoto M. Silencing the constitutive active transcription
factor CREB by the LKB1-SIK signaling cascade. FEBS J.
2006 Jun;273(12):2730-48
Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol.
2006 Dec;18(6):598-608
Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS,
Bare O, Labow M, Spiegelman B, Stevenson SC. Transducer
of regulated CREB-binding proteins (TORCs) induce PGC1alpha transcription and mitochondrial biogenesis in muscle
cells. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):1437984
Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR,
Simpson ER. Subcellular localization of cyclic AMP-responsive
element binding protein-regulated transcription coactivator 2
provides a link between obesity and breast cancer in
postmenopausal women. Cancer Res. 2009 Jul 1;69(13):53929
References
Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia
L, Hogenesch JB, Montminy M. TORCs: transducers of
regulated CREB activity. Mol Cell. 2003 Aug;12(2):413-23
Brown KA, Simpson ER. Obesity and breast cancer: progress
to understanding the relationship. Cancer Res. 2010 Jan
1;70(1):4-7
Sofi M, Young MJ, Papamakarios T, Simpson ER, Clyne CD.
Role of CRE-binding protein (CREB) in aromatase expression
in breast adipose. Breast Cancer Res Treat. 2003
Jun;79(3):399-407
This article should be referenced as such:
Brown KA, Samarageewa N. CRTC2 (CREB regulated
transcription coactivator 2). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(12):1104-1105.
Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G,
Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H,
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
1105