Negative control of keratinocyte differentiation by Rho/CRIK signaling coupled with up-regulation of KyoT1/2 (FHL1) expression

Grossi, Maddalena; Hiou‐Feige, Agnès; Vignano, Alice Tommasi di; Calautti, Enzo; Ostano, Paola; Lee, Sam; Chiorino, Giovanna; Dotto, G. Paolo

doi:10.1073/pnas.0505011102

Cited by 28 publications

(29 citation statements)

References 32 publications

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“…Thus, our results suggest that in human cultured keratinocytes Rac1 exerts negative control on the epidermal differentiation without influencing cell proliferation. Our results demonstrate similar effects of Rac1 inhibition with those established by Grossi et al [2005] after inhibition of Rho A, B, and C.…”

Section: Rac1 In Normal Human Adult Keratinocytessupporting

confidence: 82%

“…Author Proof A physiology, well beyond the establishment of cell-cell adhesion [Benitah et al, 2005;Grossi et al, 2005;Chrostek et al, 2006]. The main purpose of our current study was to assess in cultured human keratinocytes whether Rac1 functions in controlling growth/differentiation in this cell type and to compare our results with previous data obtained with other Rac1-related Rho family members, Rho-A, -B, and -C or with Rac1 itself in mouse mutants.…”

Section: Rac1 In Normal Human Adult Keratinocytesmentioning

confidence: 91%

“…For instance, Rho function on distinct transduction pathways to coordinate control on cytoskeletal reorganizations and growth/differentiation processes. The three best studied Rho family members, Rho-A, -B, and -C have been found to promote the establishment of epithelial adhesion and simultaneously exert strict control on the epidermal differentiation process [Braga et al, 1997;Grossi et al, 2005]. The selective inhibition of Rho-A, -B, and -C by bacterial toxin C3 causes premature differentiation of growing keratinocytes from mouse and human origins [Grossi et al, 2005].…”

mentioning

confidence: 99%

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confidence: 99%

“…Because Grossi et al [2005] found in their study that Rho-A, -B, and -C exert the negative control on keratinocytes differentiation through activation of their effector protein, CRIK kinase, the involvement of CRIK kinase in the control exerted by Rac1 on keratinocyte differentiation should now be investigated, especially since an active mutant form of Rac1 has been found to increase CRIK kinase activity [Di Cunto et al, 1998]. Finally, it must be noticed that Grossi et al [2005] have proposed that Rho/CRIK pathway is of significance in vivo under conditions such as wound healing, when the normal differentiation process is arrested and/or reversed. Hence, the very recently illustrated role of Rac1 in epidermal wound healing [Tscharntke et al, 2007] and the significant impairment of epidermal hyperproliferation during wound healing in absence of Myc [Zanet et al, 2005] concur to suggest that the functional interaction between Rac1 and c-myc might be required for epidermal hyperproliferation during wound-healing.…”

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confidence: 99%

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The inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes

Nikolova

Mitev

Minner

et al. 2007

J of Cellular Biochemistry

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Rac1 is a Rho subfamily small GTPase which is highly expressed in epidermal keratinocytes. In mice the significance of Rac1 for the maintenance of the epidermis has been controversial. In keratinocytes from human origin, the role of Rac1 in the control of growth/differentiation is still obscure. In this study we used RNA interference to induce specific inhibition of Rac1 expression in cultured human keratinocytes and analyzed the consequences on proliferation and differentiation. We found that the autocrine proliferation of keratinocytes is unaltered by Rac1 silencing. However, the suppression of Rac1 induced premature differentiation as revealed by the expression of markers (keratin 10, involucrin), but the involved mechanism is independent of the activity of p38 mitogen-activated protein kinase. Rather, we found that the effects of Rac1 silencing on keratinocytes differentiation are concomitant with negative regulation of the Ser62/Thr58 phosphorylation on the transcription factor c-myc, a mechanism known to control post-translational stability of the c-myc protein. Thus, in growing human keratinocytes, Rac1 could impede the expression of premature differentiation markers, probably by exerting positive control on c-myc activity and its binding to specific promoters.

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Section: Rac1 In Normal Human Adult Keratinocytessupporting

confidence: 82%

Section: Rac1 In Normal Human Adult Keratinocytesmentioning

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes

Nikolova

Mitev

Minner

et al. 2007

J of Cellular Biochemistry

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Cancer Stem Cells and Skin Cancer

Porta

2009

Stem Cells and Cancer

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Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans

et al. 2016

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Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two consanguineous families segregating the phenotype of severe primary microcephaly, spasticity and failure to thrive had overlapping autozygomes in which exome sequencing identified homozygous splicing variants in CIT that segregate with the phenotype within each family. CIT encodes citron, an effector of the Rho signaling that is required for cytokinesis specifically in proliferating neuroprogenitors, as well as for postnatal brain development. In agreement with the critical role assigned to the kinase domain in effecting these biological roles, we show that both splicing variants predict variable disruption of this domain. The striking phenotypic overlap between CIT-mutated individuals and the knockout mice and rats that are specifically deficient in the kinase domain supports the proposed causal link between CIT mutation and primary microcephaly in humans.

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Negative control of keratinocyte differentiation by Rho/CRIK signaling coupled with up-regulation of KyoT1/2 (FHL1) expression

Cited by 28 publications

References 32 publications

The inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes

The inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes

Cancer Stem Cells and Skin Cancer

Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans

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