Molecular mechanism of size control in development and human diseases

Yang, Xiaolong; Xu, Tian

doi:10.1038/cr.2011.63

Cited by 65 publications

(59 citation statements)

References 176 publications

(196 reference statements)

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“…If Hippo signaling is only involved in inhibiting cell division, loss of Hippo signaling would result in extra cells that are smaller than normal cells. By altering activities of some cell-cycle regulators, it has been previously shown that an increase of cell division rate was insufficient to drive cellular growth, and therefore, cell division and cellular growth can be separately regulated (reviewed by Yang and Xu, 2011). In the case of Hippo signaling, this growthinhibitory pathway appears to play an active role to negatively control both cell division and cellular growth.…”

Section: Discussionmentioning

confidence: 96%

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Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila

Deng

Lai

2012

Developmental Biology

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Tissue growth is achieved through coordinated cellular growth, cell division and apoptosis. Hippo signaling is critical for monitoring tissue growth during animal development. Loss of Hippo signaling leads to tissue overgrowth due to continuous cell proliferation and block of apoptosis. As cells lacking Hippo signaling are similar in size compared to normal cells, cellular growth must be properly maintained in Hippo signaling-deficient cells. However, it is not clear how Hippo signaling might regulate cellular growth. Here we show that loss of Hippo signaling increased Akt (also called Protein Kinase B, PKB) expression and activity, whereas activation of Hippo signaling reduced Akt expression in developing tissues in Drosophila. While yorkie (yki) is sufficient to increase Akt expression, Akt up-regulation caused by the loss of Hippo signaling is strongly dependent on yki, indicating that Hippo signaling negatively regulates Akt expression through Yki inhibition. Consistently, genetic analysis revealed that Akt plays a critical role in facilitating growth of Hippo signaling-defective tissues. Thus, Hippo signaling not only blocks cell division and promotes apoptosis, but also regulates cellular growth by inhibiting the Akt pathway activity.

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Section: Discussionmentioning

confidence: 96%

“…en-Galt4 drives expression of UAS transgenes in the P compartment. Hietakangas and Cohen, 2009;Yang and Xu, 2011). The observation that tumor cells generated by losing Hippo signaling activity are similar in size compared to normal cells (e.g.…”

Section: Genetic Interaction Between Akt and Mats In Regulating Cell mentioning

confidence: 96%

Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila

Deng

Lai

2012

Developmental Biology

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“…This is reflective of the robust nature of the developmental process in the face of inevitable variations at all levels, ranging from molecular to organismal and environmental levels (Patel and Lall, 2002;Flatt, 2005;Martinez Arias and Hayward, 2006;Hendrikse et al, 2007;Lander, 2007;Lott et al, 2007). A full, mechanistic understanding of scaling requires knowledge about two distinct aspects of development: specification of scaled patterns and coordinated tissue growth (Su and O'Farrell, 1998;Day and Lawrence, 2000;Crickmore and Mann, 2008;BenZvi et al, 2011;Wartlick et al, 2011;Yang and Xu, 2011;BaenaLopez et al, 2012). Recent quantitative studies have uncovered insights into scaled patterning specification in Drosophila (Houchmandzadeh et al, 2002;Gregor et al, 2005;He et al, 2008;Manu et al, 2009;Cheung et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Adaptation of the length scale and amplitude of the Bicoid gradient profile to achieve robust patterning in abnormally large Drosophila melanogaster embryos

et al. 2014

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The formation of patterns that are proportional to the size of the embryo is an intriguing but poorly understood feature of development. Molecular mechanisms controlling such proportionality, or scaling, can be probed through quantitative interrogations of the properties of morphogen gradients that instruct patterning. Recent studies of the Drosophila morphogen gradient Bicoid (Bcd), which is required for anterior-posterior (AP) patterning in the early embryo, have uncovered two distinct ways of scaling. Whereas between-species scaling is achieved by adjusting the exponential shape characteristic of the Bcd gradient profile, namely, its length scale or length constant (λ), within-species scaling is achieved through adjusting the profile's amplitude, namely, the Bcd concentration at the anterior (B 0 ). Here, we report a case in which Drosophila melanogaster embryos exhibit Bcd gradient properties uncharacteristic of their size. The embryos under investigation were from a pair of inbred lines that had been artificially selected for egg size extremes. We show that B 0 in the large embryos is uncharacteristically low but λ is abnormally extended. Although the large embryos have more total bcd mRNA than their smaller counterparts, as expected, its distribution is unusually broad. We show that the large and small embryos develop gene expression patterns exhibiting boundaries that are proportional to their respective lengths. Our results suggest that the large-egg inbred line has acquired compensating properties that counteract the extreme length of the embryos to maintain Bcd gradient properties necessary for robust patterning. Our study documents, for the first time to our knowledge, a case of within-species Bcd scaling achieved through adjusting the gradient profile's exponential shape characteristic, illustrating at a molecular level how a developmental system can follow distinct operational paths towards the goal of robust and scaled patterning.

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“…[1][2][3][4] However, excessive insulin signaling caused by hyperinsulinemia or overexpression of insulin receptor (IR) has been linked to cancer progression. 5 Recent epidemiological and experimental studies have demonstrated that hyperinsulinemia is a major cancer risk factor among many type 2 diabetes mellitus patients and obese individuals.…”

Section: Introductionmentioning

confidence: 99%

Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

et al. 2013

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Insulin and insulin-like growth factor-1 signaling have fundamental roles in energy metabolism, growth and development. Recent research suggests hyperactive insulin receptor (IR) and hyperinsulinemia are cancer risk factors. However, the mechanisms that account for the link between the hyperactive insulin signaling and cancer risk are not well understood. Here we show that an insulin-like signaling inhibits the DAF-18/(phosphatase and tensin homolog) PTEN tumour suppressor in Caenorhabditis elegans and that this regulation is conserved in human breast cancer cells. We show that inhibiting the IR increases PTEN protein levels, while increasing insulin signaling decreases PTEN protein levels. Our results show that the kinase region of IRb subunit physically binds to PTEN and phosphorylates on Y27 and Y174. Our genetic results also show that DAF-2/IR negatively regulates DAF-18/PTEN during C. elegans axon guidance. As PTEN is an important tumour suppressor, our results therefore suggest a possible mechanism for increased cancer risk observed in hyperinsulinemia and hyperactive IR individuals.

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Molecular mechanism of size control in development and human diseases

Cited by 65 publications

References 176 publications

Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila

Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila

Adaptation of the length scale and amplitude of the Bicoid gradient profile to achieve robust patterning in abnormally large Drosophila melanogaster embryos

Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

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