Identification of Fat4 as a candidate tumor suppressor gene in breast cancers

Qi, Chao; Zhu, Yiwei Tony; Hu, Liping; Zhu, Yijun

doi:10.1002/ijc.23775

Cited by 99 publications

(100 citation statements)

References 33 publications

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“…Yorkie) of lats have been identified, which constitute a novel signaling pathway called Hippo-LATS pathway that plays important roles in organ size control by regulation of cell proliferation [22][23][24][25][26][27][28][29][30]. Most of the mammalian homologs of the components of the Drosophila Hippo-LATS pathway have been identified (Fat4 for Fat; Merlin for Merlin, FRMD6 for Expanded, MOB1 for MATS; Mst1/2 for Hippo, hWW45 for Salvador; LATS1/2 for lats; YAP or TAZ for Yorkie) [25,[31][32][33][34][35][36][37][38][39][40][41][42]. Most significantly, it has been shown that conditional knockdown of merlin, Mst1/2, or WW45 (Salvador), or overexpression of YAP in the liver results in increased liver size in mice [25,33,43,44], suggesting that the Hippo-LATS signaling pathway is an evolutionally conserved pathway regulating animal organ size by regulating cell numbers.…”

Section: The Role Of Cell Proliferation In Size Controlmentioning

confidence: 99%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.

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Section: The Role Of Cell Proliferation In Size Controlmentioning

confidence: 99%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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“…Mutation of many of these genes has been implicated in human cancers (McClatchey and Giovannini, 2005;Harvey and Tapon, 2007;Yokoyama et al, 2008), Fat4/FatJ has recently been implicated as a breast tumour suppressor gene (Qi et al, 2009), and Yap1 expression and nuclear localisation is upregulated in Shh-associated medulloblastomas (Fernandez et al, 2009). Recent studies show that the Hippo pathway controls the number of neuronal progenitors in the neural tube by influencing cell proliferation and apoptosis (Cao et al, 2008).…”

Section: Research Articlementioning

confidence: 99%

FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools

et al. 2011

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SUMMARYThe size, composition and functioning of the spinal cord is likely to depend on appropriate numbers of progenitor and differentiated cells of a particular class, but little is known about how cell numbers are controlled in specific cell cohorts along the dorsoventral axis of the neural tube. Here, we show that FatJ cadherin, identified in a large-scale RNA interference (RNAi) screen of cadherin genes expressed in the neural tube, is localised to progenitors in intermediate regions of the neural tube. Loss of function of FatJ promotes an increase in dp4-vp1 progenitors and a concomitant increase in differentiated Lim1 + /Lim2 + neurons. Our studies reveal that FatJ mediates its action via the Hippo pathway mediator Yap1: loss of downstream Hippo components can rescue the defect caused by loss of FatJ. Together, our data demonstrate that RNAi screens are feasible in the chick embryonic neural tube, and show that FatJ acts through the Hippo pathway to regulate cell numbers in specific subsets of neural progenitor pools and their differentiated progeny.

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“…75 Furthermore, Fat4 is a candidate tumor suppressor whose expression is lost in a fraction of human breast tumor cell lines and primary tumors. 76 …”

Section: How Does the Hpo Pathway Read The Spatial And Temporal Signals?mentioning

confidence: 99%

Hippo signaling pathway and organ size control

Zhang¹,

Tao²,

Jen³

2009

Fly

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Initially discovered in Drosophila, the Hippo (Hpo) pathway has been recognized as a conserved signaling pathway that controls organ size during development by restricting cell growth and proliferation and by promoting apoptosis. In addition, abnormal activities of several Hpo pathway components have been implicated in human cancer. Here, we review the current understanding of the molecular and cellular basis of Hpo signaling in development and tumorigenesis, and discuss how the Hpo pathway integrates spatial and temporal signals to control tissue growth and organ size.Different organs exhibit characteristic size, which is determined by the number and size of their constituent cells. 1 How the organ size is controlled during animal development has been a fascinating problem in modern biology. The control of organ size depends on a delicate balance of cell proliferation and cell death, which are properly coordinated in response to both global and local stimuli. Although tissue growth is influenced by environmental factors such as hormonal signals and nutrients, organ-intrinsic mechanisms also play important roles. By genetic screens for, and characterization of, mutations that cause tissue overgrowth in Drosophila, several signaling pathways, including the Hpo pathway, have been unraveled as organ-intrinsic mechanisms that control organ size. 2 Finding Hippo-An Emerging Size Control PathwayThe imaginal discs of Drosophila, which give rise to adult structures such as wings, legs and eyes, provide an attractive system to study size control. 3 Imaginal discs are specified during embryonic development but growth occurs at larval stages during which the number of cells of each disc increases exponentially. For example, a wing disc has less than 50 cells at the beginning of first instar; however, it contains over 50,000 cells at the end of third instar. Imaginal discs appear to possess intrinsic mechanisms to determine their final size and defects in these mechanisms result in overgrowth in a disc autonomous fashion. 4,5 In the past, tumor suppressor mutants were identified by genetic screens for mutations that either result in enlarged imaginal discs in homozygous late third instar larvae, or cause overgrowth of imaginal disc derivatives in mosaic flies that carry clones of homozygous mutant cells in an otherwise heterozygous background (Fig. 1). 2,6 In particular, genetic mosaic screens have led to the identification of a number of tumor suppressor genes, including warts/ large tumor suppressor (wts/lats), 7,8 salvador (sav) 9 and hpo/dMST, 10-14 which fall into an emerging tumor suppressor pathway, the so-called Hpo pathway (Fig. 2).Central to the Hpo pathway is a kinase cascade consisting of four proteins including Hpo, Sav, Wts and Mats (Fig. 2). Hpo is the Drosophila homolog of mammalian Ste20 family kinases MST1 and MST2, and forms a complex with the WW-repeat scaffolding protein Sav to phosphorylate and activate the downstream kinase Wts, a member of the Nuclear Dbf-2-related (NDR) kinase family. 7-14 Wts acts ...

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Identification of Fat4 as a candidate tumor suppressor gene in breast cancers

Cited by 99 publications

References 33 publications

Molecular mechanism of size control in development and human diseases

Molecular mechanism of size control in development and human diseases

FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools

Hippo signaling pathway and organ size control

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