Primary Cilium-Dependent and -Independent Hedgehog Signaling Inhibits p16INK4A

Bishop, Cleo L.; Bergin, Ann‐Marie; Fessart, Delphine; Borgdorff, Viola; Hatzimasoura, Elizabeth; Garbe, James C.; Stampfer, Martha R.; Koh, Joanna; Beach, David

doi:10.1016/j.molcel.2010.10.027

Cited by 54 publications

(67 citation statements)

References 53 publications

(62 reference statements)

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“…S2). No differences in proliferation were observed between the NT cells compared with any of the DSP siRNA-treated cells, in contrast to the positive control Cbx7 siRNA-treated cells, which are known to display a decrease in proliferation rate (Bishop et al, 2010). This data also eliminates the possibility that differences in cytotoxicity are the cause of the siRNA phenotypes observed, as no decrease in cell number was observed.…”

Section: The Levels Of Dspii Are Important For Hacat Cellular Adhesionmentioning

confidence: 74%

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The DSPII splice variant is critical for desmosome-mediated HaCaT keratinocyte adhesion

Cabral

Tattersall

Patel

et al. 2012

Journal of Cell Science

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SummaryDesmosomes are intercellular junctions specialised for strong adhesion that are prominent in the epidermis and heart muscle. Defective desmosomal function due to inherited mutations in the constitutive desmosomal gene desmoplakin (DSP) causes skin or heart disorders and in some instances both. Different mutations have different disease-causing molecular mechanisms as evidenced by the varying phenotypes resulting from mutations affecting different domains of the same protein, but the majority of these mechanisms remain to be determined. Here, we studied two mutations in DSP that lead to different dosages of the two major DSP splice variants, DSPI and DSPII, and compared their molecular mechanisms. One of the mutations results in total DSP haploinsufficiency and is associated with autosomal dominant striate palmoplantar keratoderma (PPK). The other leads to complete absence of DSPI and the minor isoform DSPIa but normal levels of DSPII, and is associated with autosomal recessive epidermolytic PPK, woolly hair and severe arrhythmogenic dilated cardiomyopathy. Using siRNA treatments to mimic these two mutations and additionally a DSPII-specific siRNA, we found striking differences between DSP isoforms with respect to keratinocyte adhesion upon cellular stress with DSPII being the key component in intermediate filament (IF) stability and desmosome-mediated adhesion. In addition, reduction in DSP expression reduced the amount of plakophilin 1, desmocollin (DSC) 2 and DSC3 with DSPI having a greater influence than DSPII on the expression levels of DSC3. These results suggest that the two major DSP splice variants are not completely redundant in function and that DSPII dosage is particularly important for desmosomal adhesion in the skin.

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Section: The Levels Of Dspii Are Important For Hacat Cellular Adhesionmentioning

confidence: 74%

“…siII siRNA knockdown was performed using a trans-splice site strategy, with two siRNA duplexes being designed across the DSPII-specific c.3861-c.5659 RNA junction. The Cxb7 siRNA was used as described elsewhere (Bishop et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

The DSPII splice variant is critical for desmosome-mediated HaCaT keratinocyte adhesion

Cabral

Tattersall

Patel

et al. 2012

Journal of Cell Science

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“…21,31 Given the pro-mitogenic role established for Hh, 32,33 we therefore tested whether inhibition of Hh through the small molecule inhibitor, cyclopamine, 34 affected fibroblast proliferation, as determined by Ki67 staining. As shown in Figure 3A and B, cyclopamine caused a decline in the proliferative index in both young and senescent BJ populations.…”

Section: Resultsmentioning

confidence: 99%

“…32 The involvement of Hh in a range of cell renewal activities throughout the lifespan of an organism has led to its being invoked as an antagonist of aging. 36 While our data indicating the involvement of Hh signaling in continued proliferation are consistent with this model, we did not observe the loss of primary cilia in senescent cells that was described in human mammary epithelial cell (HMEC) cultures.…”

Section: Discussionmentioning

confidence: 99%

Ciliary abnormalities in senescent human fibroblasts impair proliferative capacity

et al. 2014

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Somatic cells senesce in culture after a finite number of divisions indefinitely arresting their proliferation. DNA damage and senescence increase the cellular number of centrosomes, the 2 microtubule organizing centers that ensure bipolar mitotic spindles. Centrosomes also provide the basal body from which primary cilia extend to sense and transduce various extracellular signals, notably Hedgehog. Primary cilium formation is facilitated by cellular quiescence a temporary cell cycle exit, but the impact of senescence on cilia is unknown. We found that senescent human fibroblasts have increased frequency and length of primary cilia. Levels of the negative ciliary regulator CP110 were reduced in senescent cells, as were levels of key elements of the Hedgehog pathway. Hedgehog inhibition reduced proliferation in young cells with increased cilium length accompanying cell cycle arrest suggesting a regulatory function for Hedgehog in primary ciliation. Depletion of CP110 in young cell populations increased ciliation frequencies and reduced cell proliferation. These data suggest that primary cilia are potentially novel determinants of the reduced cellular proliferation that initiates senescence.

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“…Transcriptional regulators that have been reported to repress the INK4A and ARF genes expression include the T-box transcription factor TBX2, a potent repressor of mouse ARF (Jacobs et al, 2000), and the transcriptional co-repressor CtBP, which has been implicated as a direct repressor of human INK4A expression (Mroz et al, 2008). Recent work has also implicated an N-terminal fragment of the GLI2 transcription factor in the repression of INK4A by direct binding to its promoter (Bishop et al, 2010). Although these factors are known repressors of the INK4A-ARF locus, further work is required to evaluate their potential interplay with polycomb group proteins.…”

Section: Ink4amentioning

confidence: 99%