PMID- 24852887
OWN - NLM
STAT- MEDLINE
DCOM- 20150401
LR  - 20240321
IS  - 1096-3634 (Electronic)
IS  - 1084-9521 (Print)
IS  - 1084-9521 (Linking)
VI  - 33
IP  - 100
DP  - 2014 Sep
TI  - Context-dependent signal integration by the GLI code: the oncogenic load, 
      pathways, modifiers and implications for cancer therapy.
PG  - 93-104
LID - S1084-9521(14)00130-X [pii]
LID - 10.1016/j.semcdb.2014.05.003 [doi]
AB  - Canonical Hedgehog (HH) signaling leads to the regulation of the GLI code: the 
      sum of all positive and negative functions of all GLI proteins. In humans, the 
      three GLI factors encode context-dependent activities with GLI1 being mostly an 
      activator and GLI3 often a repressor. Modulation of GLI activity occurs at 
      multiple levels, including by co-factors and by direct modification of GLI 
      structure. Surprisingly, the GLI proteins, and thus the GLI code, is also 
      regulated by multiple inputs beyond HH signaling. In normal development and 
      homeostasis these include a multitude of signaling pathways that regulate 
      proto-oncogenes, which boost positive GLI function, as well as tumor suppressors, 
      which restrict positive GLI activity. In cancer, the acquisition of oncogenic 
      mutations and the loss of tumor suppressors - the oncogenic load - regulates the 
      GLI code toward progressively more activating states. The fine and reversible 
      balance of GLI activating GLI(A) and GLI repressing GLI(R) states is lost in 
      cancer. Here, the acquisition of GLI(A) levels above a given threshold is 
      predicted to lead to advanced malignant stages. In this review we highlight the 
      concepts of the GLI code, the oncogenic load, the context-dependency of GLI 
      action, and different modes of signaling integration such as that of HH and EGF. 
      Targeting the GLI code directly or indirectly promises therapeutic benefits 
      beyond the direct blockade of individual pathways.
CI  - Copyright (c) 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Aberger, Fritz
AU  - Aberger F
AD  - Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 
      5020 Salzburg, Austria. Electronic address: fritz.aberger@sbg.ac.at.
FAU - Ruiz i Altaba, Ariel
AU  - Ruiz i Altaba A
AD  - Department of Genetic Medicine and Development, University of Geneva Medical 
      School, 8242 CMU, 1 rue Michel Servet, CH-1211 Geneva, Switzerland. Electronic 
      address: ariel.ruizaltaba@unige.ch.
LA  - eng
GR  - P 25629/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Review
DEP - 20140519
PL  - England
TA  - Semin Cell Dev Biol
JT  - Seminars in cell & developmental biology
JID - 9607332
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
SB  - IM
MH  - Animals
MH  - Carcinogenesis/genetics/*metabolism
MH  - Carcinoma, Basal Cell/drug therapy/genetics/*metabolism
MH  - Colonic Neoplasms/drug therapy/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Hedgehog Proteins/physiology
MH  - Humans
MH  - Molecular Targeted Therapy
MH  - *Signal Transduction
MH  - Transcription Factors/*physiology
MH  - Zinc Finger Protein GLI1
PMC - PMC4151135
OTO - NOTNLM
OT  - Cancer
OT  - Development
OT  - GLI transcription factors
OT  - Hedgehog-GLI signaling
OT  - Oncogenes
OT  - Signal transduction
OT  - Signaling integration
OT  - Stem cells
EDAT- 2014/05/24 06:00
MHDA- 2015/04/02 06:00
PMCR- 2014/09/01
CRDT- 2014/05/24 06:00
PHST- 2014/02/19 00:00 [received]
PHST- 2014/05/12 00:00 [accepted]
PHST- 2014/05/24 06:00 [entrez]
PHST- 2014/05/24 06:00 [pubmed]
PHST- 2015/04/02 06:00 [medline]
PHST- 2014/09/01 00:00 [pmc-release]
AID - S1084-9521(14)00130-X [pii]
AID - 10.1016/j.semcdb.2014.05.003 [doi]
PST - ppublish
SO  - Semin Cell Dev Biol. 2014 Sep;33(100):93-104. doi: 10.1016/j.semcdb.2014.05.003. 
      Epub 2014 May 19.