PMID- 21955824
OWN - NLM
STAT- MEDLINE
DCOM- 20120221
LR  - 20211203
IS  - 1471-213X (Electronic)
IS  - 1471-213X (Linking)
VI  - 11
DP  - 2011 Sep 29
TI  - Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial 
      tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo 
      pathway signaling.
PG  - 57
LID - 10.1186/1471-213X-11-57 [doi]
AB  - BACKGROUND: Epithelial neoplasias are associated with alterations in cell 
      polarity and excessive cell proliferation, yet how these neoplastic properties 
      are related to one another is still poorly understood. The study of Drosophila 
      genes that function as neoplastic tumor suppressors by regulating both of these 
      properties has significant potential to clarify this relationship. RESULTS: Here 
      we show in Drosophila that loss of Scribbled (Scrib), a cell polarity regulator 
      and neoplastic tumor suppressor, results in impaired Hippo pathway signaling in 
      the epithelial tissues of both the eye and wing imaginal disc. scrib mutant 
      tissue overgrowth, but not the loss of cell polarity, is dependent upon defective 
      Hippo signaling and can be rescued by knockdown of either the TEAD/TEF family 
      transcription factor Scalloped or the transcriptional coactivator Yorkie in the 
      eye disc, or reducing levels of Yorkie in the wing disc. Furthermore, loss of 
      Scrib sensitizes tissue to transformation by oncogenic Ras-Raf signaling, and 
      Yorkie-Scalloped activity is required to promote this cooperative tumor 
      overgrowth. The inhibition of Hippo signaling in scrib mutant eye disc clones is 
      not dependent upon JNK activity, but can be significantly rescued by reducing 
      aPKC kinase activity, and ectopic aPKC activity is sufficient to impair Hippo 
      signaling in the eye disc, even when JNK signaling is blocked. In contrast, warts 
      mutant overgrowth does not require aPKC activity. Moreover, reducing endogenous 
      levels of aPKC or increasing Scrib or Lethal giant larvae levels does not promote 
      increased Hippo signaling, suggesting that aPKC activity is not normally rate 
      limiting for Hippo pathway activity. Epistasis experiments suggest that Hippo 
      pathway inhibition in scrib mutants occurs, at least in part, downstream or in 
      parallel to both the Expanded and Fat arms of Hippo pathway regulation. 
      CONCLUSIONS: Loss of Scrib promotes Yorkie/Scalloped-dependent epithelial tissue 
      overgrowth, and this is also important for driving cooperative tumor overgrowth 
      with oncogenic Ras-Raf signaling. Whether this is also the case in human cancers 
      now warrants investigation since the cell polarity function of Scrib and its 
      capacity to restrain oncogene-mediated transformation, as well as the tissue 
      growth control function of the Hippo pathway, are conserved in mammals.
FAU - Doggett, Karen
AU  - Doggett K
AD  - Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, 7 St 
      Andrews Place, East Melbourne, 3002, Victoria, Australia.
FAU - Grusche, Felix A
AU  - Grusche FA
FAU - Richardson, Helena E
AU  - Richardson HE
FAU - Brumby, Anthony M
AU  - Brumby AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110929
PL  - England
TA  - BMC Dev Biol
JT  - BMC developmental biology
JID - 100966973
RN  - 0 (Drosophila Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Scrib protein, Drosophila)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (Yki protein, Drosophila)
RN  - 0 (sd protein, Drosophila)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (hpo protein, Drosophila)
RN  - EC 2.7.11.1 (raf Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 3.6.5.2 (Oncogene Protein p21(ras))
SB  - IM
MH  - Animals
MH  - Cell Polarity/*genetics
MH  - Cell Proliferation
MH  - Drosophila Proteins/deficiency/genetics/*metabolism
MH  - Drosophila melanogaster/cytology/genetics/*metabolism
MH  - Epithelial Cells/metabolism
MH  - Eye/embryology
MH  - Intracellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Membrane Proteins
MH  - Mutation
MH  - Nuclear Proteins/deficiency/genetics
MH  - Oncogene Protein p21(ras)/metabolism
MH  - Protein Kinase C/biosynthesis
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - *Signal Transduction
MH  - Trans-Activators/deficiency/genetics
MH  - Transcription Factors/deficiency/genetics
MH  - Tumor Suppressor Proteins/deficiency/genetics/*metabolism
MH  - Wings, Animal/embryology
MH  - YAP-Signaling Proteins
MH  - raf Kinases/metabolism
PMC - PMC3206446
EDAT- 2011/10/01 06:00
MHDA- 2012/02/22 06:00
PMCR- 2011/09/29
CRDT- 2011/09/30 06:00
PHST- 2011/03/21 00:00 [received]
PHST- 2011/09/29 00:00 [accepted]
PHST- 2011/09/30 06:00 [entrez]
PHST- 2011/10/01 06:00 [pubmed]
PHST- 2012/02/22 06:00 [medline]
PHST- 2011/09/29 00:00 [pmc-release]
AID - 1471-213X-11-57 [pii]
AID - 10.1186/1471-213X-11-57 [doi]
PST - epublish
SO  - BMC Dev Biol. 2011 Sep 29;11:57. doi: 10.1186/1471-213X-11-57.