Decreased Srcasm expression in hyperproliferative cutaneous lesions

Meulener, Marc C.; Ayli, Elias E.; Elenitsas, Rosalie; Seykora, John T.

doi:10.1111/j.1600-0560.2008.01035.x

Cited by 9 publications

(6 citation statements)

References 14 publications

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“…These findings suggest that the inverse relationship between SFK activity and Srcasm levels may represent a general mechanism of carcinogenesis. Supporting this hypothesis, Srcasm levels are decreased in human basal cell carcinomas and in esophageal SCC tumor cell lines compared with non-neoplastic keratinocyte lines (data not shown) (45). …”

Section: Discussionmentioning

confidence: 81%

Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

Zhao

Marshall

et al. 2009

Cancer Research

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Src family tyrosine kinases (SFK) regulate cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell carcinomas (SCC) and its precursors. The elevated SFK activity in cutaneous SCCs was modeled using K14-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses, SCC in situ, and SCCs, respectively. Lesional tissue showed increased levels of activated SFKs, PDK1, STAT3, and ERK1/2, whereas Notch1/ NICD protein and transcript levels were decreased. p53 levels also were decreased in SCC in situ and SCCs. Increasing Srcasm levels using a K14-Fyn Y528F/K14-Srcasm double transgenic model markedly inhibited cutaneous neoplasia.

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Section: Discussionmentioning

confidence: 81%

Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

Zhao

Marshall

et al. 2009

Cancer Research

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“…and T.H). For each specimen, staining index was assessed by multiplying the staining intensity score by the extent of staining score as previously reported . Staining intensity was graded as follows: 1, none; 2, weak; 3, moderate; 4, strong.…”

Section: Methodsmentioning

confidence: 99%

Expression profiles of cortisol‐inactivating enzyme, 11β‐hydroxysteroid dehydrogenase‐2, in human epidermal tumors and its role in keratinocyte proliferation

Terao

Itoi

Murota

et al. 2013

Experimental Dermatology

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The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) catalyzes the interconversion between hormonally active cortisol and inactive cortisone within cells. There are two isozymes: 11β-HSD1 activates cortisol from cortisone and 11β-HSD2 inactivates cortisol to cortisone. 11β-HSD1 was recently discovered in skin, and we subsequently found that the enzyme negatively regulates keratinocyte proliferation. We verified 11β-HSD1 and 11β-HSD2 expression in benign and malignant skin tumors and investigated the role of 11β-HSD in skin tumor pathogenesis. Randomly selected formalin-fixed sections of skin lesions of seborrheic keratosis (SK), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) were stained with 11β-HSD1 and 11β-HSD2 antibodies, and 11β-HSD expression was also evaluated in murine epidermis in which hyperproliferation was induced by 12-O-tetradecanoylphorbol-13 acetate (TPA). We observed that 11β-HSD1 expression was decreased in all SK, SCC, and BCC lesions compared with unaffected skin. Conversely, 11β-HSD2 expression was increased in SK and BCC but not in SCC. Overexpression of 11β-HSD2 in keratinocytes increased cell proliferation. In the murine model, 11β-HSD1 expression was decreased in TPA-treated hyperproliferative skin. Our findings suggest that 11β-HSD1 expression is decreased in keratinocyte proliferative conditions, and 11β-HSD2 expression is increased in basal cell proliferating conditions, such as BCC and SK. Assessing 11β-HSD1 and 11β-HSD2 expression could be a useful tool for diagnosing and characterizing skin tumors.

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“…Interestingly, reduced levels of TOM1L1 have also been reported in human cutaneous neoplasia (Meulener et al, 2009), implying a negative role of TOM1L1 in cell proliferation. Therefore, it will be interesting to determine as to how TOM1L1 impacts cancer cell growth.…”

Section: Tom1l1 and Clathrin: Regulation Of Egfr Signallingmentioning

confidence: 94%

Clathrin and TOM1L1 regulate epidermal growth factor receptor signaling at the plasma membrane

Judge¹

2021

Preprint

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Epidermal growth factor (EGF) receptor (EGFR) controls many aspects of cell physiology via the activation of intracellular signaling pathways. Aberrant EGFR signaling and overexpression of EGFR is a characteristic of various cancer types. Ligandbound EGFR elicits phosphorylation of Gab1, which activates phosphatidylinositol-3-kinase (PI3K), which in turn leads to Akt phosphorylation and activation. Akt is a central regulator of cell survival and metabolism. Rapidly upon binding EGF, the receptor is recruited to clathrin-coated pits (CCPs), eventually leading to EGFR endocytosis. As such, receptor-proximal EGFR signaling occurs while the receptor is enriched with CCPs at the plasma membrane. We have recently found that clathrin, but not receptor endocytosis, is required for EGF-stimulated phosphorylation of Akt, yet how clathrin controls EGFR signaling at the plasma membrane remains poorly understood. Clathrin interacts with and recruits numerous proteins to the plasma membrane. To examine how specific clathrin-interacting proteins may underlie the requirement for clathrin in EGFR signaling, I have examined the role of TOM1L1, which interacts with clathrin, EGFR and Src-family kinases (SFKs) through distinct domains. SiRNA gene silencing of TOM1L1 impairs EGF-stimulated Akt phosphorylation, as did expression of a dominant-interfering mutant of TOM1L1 deficient in clathrin binding. Using fluorescent labeling of clathrin, TOM1L1 and other signaling intermediates coupled to total internal reflection fluorescence microscopy; I found that CCPs are enriched in TOM1L1 and phosphorylated Gab1 upon EGF stimulation. These findings indicate that the clathrin-binding adaptor TOM1L1 regulates EGF-stimulated Akt phosphorylation, thus revealing a novel molecular mechanism of regulation of EGFR signaling at the plasma membrane.

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Decreased Srcasm expression in hyperproliferative cutaneous lesions

Cited by 9 publications

References 14 publications

Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

Expression profiles of cortisol‐inactivating enzyme, 11β‐hydroxysteroid dehydrogenase‐2, in human epidermal tumors and its role in keratinocyte proliferation

Clathrin and TOM1L1 regulate epidermal growth factor receptor signaling at the plasma membrane

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