Epidermal Ras blockade demonstrates spatially localized Ras promotion of proliferation and inhibition of differentiation

Dajee, Maya; Tarutani, Masahito; Deng, Helen; Cai, Ti; Khavari, Paul A.

doi:10.1038/sj.onc.1205287

Cited by 86 publications

(101 citation statements)

References 55 publications

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“…This activity seemed specific, as pPTEN, pAkt, pGSK3b and also pp38 and pJNK phosphorylation levels were not affected at all by NaHS. From the functional point of view, in agreement with data from other groups, [35][36][37] MEK inhibition (by U0126) suggested that the MEK-ERK signaling has a major role in the control of NCTC cell proliferation. The antiproliferative effects of NaHS are now well documented at least in lymphocytes in vitro [38][39] and in smooth 41 and to increased c-Jun, Raf, MAPKK, MEK and ERK mRNA expression levels in IEC-18 rat intestinal cells.…”

Section: H2s Downregulates Erk In Keratinocytessupporting

confidence: 79%

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

Gobbi

Ricci

Malinverno

et al. 2009

Laboratory Investigation

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The effects of exogenous hydrogen sulfide (H 2 S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H 2 S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation and adhesion of mature cells. As a mechanistic explanation of these effects, we show at the molecular level that (i) H 2 S reduces the Raf/MAPK kinase/ERK signaling pathway; (ii) the reduced adhesion of sulfur-treated cells is associated to the downregulation of the expression of b4, a2 and a6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. One specific interest of the effects of sulfurs on keratinocytes derives from the potential applications of the results, as sulfur is able to penetrate the skin and a sulfur-rich balneotherapy has been known for long to be effective in the treatment of psoriasis. Thus, the relevance of our findings to the pathophysiology of psoriasis was tested in vivo by treating psoriatic lesions with sulfurs at a concentration comparable to that most commonly found in sulfurous natural springs. In agreement with the in vitro observations, the immunohistochemical analysis of patient biopsies showed a specific downregulation of ERK activation levels, the key molecular event in the sulfur-induced effects on keratinocytes.

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Section: H2s Downregulates Erk In Keratinocytessupporting

confidence: 79%

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

Gobbi

Ricci

Malinverno

et al. 2009

Laboratory Investigation

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“…In normal keratinocytes, ras expression is required for basal cell proliferation but not for cells in the suprabasal layers where they are undergoing differentiation (Dajee et al, 2002). This observation suggests that papillomaviruses require the activation of signal transduction pathways that are relevant to proliferation for their normal life cycle.…”

Section: Discussionmentioning

confidence: 77%

Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A

et al. 2005

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Protein kinase B (PKB) or Akt is one of several second messenger kinases that are activated by cell attachment and growth factor signaling, and that transmit signals to the cell nucleus to inhibit apoptosis and thereby increase cell survival during proliferation. Other viral proteins target this pathway by increasing PKB/Akt phosphorylation, and this pathway has been implicated in the transformation of human keratinocytes by HPV E6 and E7, together with activated notch 1. Here, we examine how HPV E7 expression affects the phosphorylation of PKB. We show that HPV-16 E7 increases the level of phosphorylation of PKB in response to serum stimulation, by a mechanism independent of downregulation of PTEN phosphatase, a known inhibitor of the PI3K (PI3 kinase) pathway. The use of specific antibodies shows that some proportion of PKB/Akt that is phosphorylated both on threonine 308 and serine 473 is maintained in the presence of E7 in a PI3 kinase-independent manner, and is activated for phosphorylation of BAD, a known downstream target of PKB/Akt. Use of E7 mutants has ruled out both an inhibition of IGFBP-3, a known E7 target and PKB/Akt modulator, and the interaction of E7 with cellular pocket proteins, as being the mechanism for the PKB/Akt stimulation. PKB binds PP2A and is a known substrate of PP2A. Here, we show that HPV E7 also binds to both the 35 kDa catalytic and 65 kDa structural subunits of PP2A, an interaction that sequesters these subunits and inhibits their interaction with PKB, thereby maintaining PKB/Akt signaling by inhibiting its dephosphorylation.

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“…We then introduced into HKe-3 cells a regulatable RAS construct made up of mutant HRAS fused to the oestrogen receptor (ER) ligand-binding domain that is conditionally responsive to 4-hydroxytamoxifen (OHT; Dajee et al, 2002). Addition of OHT acutely activates the RAS pathway in HKe-3 cells expressing ER:HRAS V12.…”

Section: Snail2 In Ras Induced Emtmentioning

confidence: 99%

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

et al. 2010

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Activating mutations in the KRAS gene are among the most prevalent genetic changes in human cancers. To identify synthetic lethal interactions in cancer cells harbouring mutant KRAS, we performed a large-scale screen in isogenic paired colon cancer cell lines that differ by a single allele of mutant KRAS using an inducible short hairpin RNA interference library. Snail2, a zinc finger transcriptional repressor encoded by the SNAI2 gene, was found to be selectively required for the long-term survival of cancer cells with mutant KRAS that have undergone epithelial-mesenchymal transition (EMT), a transdifferentiation event that is frequently seen in advanced tumours and is promoted by RAS activation. Snail2 expression is regulated by the RAS pathway and is required for EMT. Our findings support Snail2 as a possible target for the treatment of the broad spectrum of human cancers of epithelial origin with mutant RAS that have undergone EMT and are characterized by a high degree of chemoresistance and radioresistance.

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Epidermal Ras blockade demonstrates spatially localized Ras promotion of proliferation and inhibition of differentiation

Cited by 86 publications

References 55 publications

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

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