PMID- 23686138
OWN - NLM
STAT- MEDLINE
DCOM- 20140206
LR  - 20211021
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 20
IP  - 8
DP  - 2013 Aug
TI  - Interaction between the TP63 and SHH pathways is an important determinant of 
      epidermal homeostasis.
PG  - 1080-8
LID - 10.1038/cdd.2013.41 [doi]
AB  - Deregulation of the hedgehog (HH) pathway results in overexpression of the GLI 
      target BCL2 and is an initiating event in specific tumor types including basal 
      cell carcinoma of the skin. Regulation of the HH pathway during keratinocyte 
      differentiation is not well understood. We measured HH pathway activity in 
      response to differentiation stimuli in keratinocytes. An upregulation of 
      suppressor of fused (SUFU), a negative regulator of the HH pathway, lowered HH 
      pathway activity and was accompanied by loss of BCL2 expression associated with 
      keratinocyte differentiation. We used in vitro and in vivo models to demonstrate 
      that DeltaNp63alpha, a crucial regulator of epidermal development, activates SUFU 
      transcription in keratinocytes. Increasing SUFU protein levels inhibited 
      GLI-mediated gene activation in suprabasal keratinocytes and promoted 
      differentiation. Loss of SUFU expression caused deregulation of keratinocyte 
      differentiation and BCL2 overexpression. Using in vivo murine models, we also 
      provide evidence of GLI-mediated regulation of the TP63 pathway. p63 expression 
      appears essential to establish an optimally functioning HH pathway. These 
      observations present a regulatory mechanism by which SUFU acts as an interacting 
      node between the HH and TP63 pathways to mediate differentiation and maintain 
      epidermal homeostasis. Disruption of this regulatory node can be an important 
      contributor to multistep carcinogenesis.
FAU - Chari, N S
AU  - Chari NS
AD  - Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Romano, R A
AU  - Romano RA
FAU - Koster, M I
AU  - Koster MI
FAU - Jaks, V
AU  - Jaks V
FAU - Roop, D
AU  - Roop D
FAU - Flores, E R
AU  - Flores ER
FAU - Teglund, S
AU  - Teglund S
FAU - Sinha, S
AU  - Sinha S
FAU - Gruber, W
AU  - Gruber W
FAU - Aberger, F
AU  - Aberger F
FAU - Medeiros, L J
AU  - Medeiros LJ
FAU - Toftgard, R
AU  - Toftgard R
FAU - McDonnell, T J
AU  - McDonnell TJ
LA  - eng
GR  - R01 CA160394/CA/NCI NIH HHS/United States
GR  - U01 CA105345/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130517
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Repressor Proteins)
RN  - 0 (Shh protein, mouse)
RN  - 0 (Sufu protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Trp63 protein, mouse)
RN  - 114100-40-2 (Bcl2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/physiology
MH  - Cell Line
MH  - Cell Proliferation
MH  - Cell Survival/physiology
MH  - Cells, Cultured
MH  - *Epidermal Cells
MH  - Epidermis/physiology
MH  - Female
MH  - Hedgehog Proteins/*physiology
MH  - Homeostasis/*physiology
MH  - In Vitro Techniques
MH  - Keratinocytes/*cytology/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred CBA
MH  - Mice, Knockout
MH  - Models, Animal
MH  - Phosphoproteins/deficiency/genetics/*physiology
MH  - Proto-Oncogene Proteins c-bcl-2/physiology
MH  - Repressor Proteins/physiology
MH  - Signal Transduction/*physiology
MH  - Trans-Activators/deficiency/genetics/*physiology
PMC - PMC3705600
EDAT- 2013/05/21 06:00
MHDA- 2014/02/07 06:00
PMCR- 2014/08/01
CRDT- 2013/05/21 06:00
PHST- 2012/10/09 00:00 [received]
PHST- 2013/03/06 00:00 [revised]
PHST- 2013/04/08 00:00 [accepted]
PHST- 2013/05/21 06:00 [entrez]
PHST- 2013/05/21 06:00 [pubmed]
PHST- 2014/02/07 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - cdd201341 [pii]
AID - 10.1038/cdd.2013.41 [doi]
PST - ppublish
SO  - Cell Death Differ. 2013 Aug;20(8):1080-8. doi: 10.1038/cdd.2013.41. Epub 2013 May 
      17.