Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 HA‐<i>ras</i> gene regulated by a mouse tyrosinase promoter

Powell, Marianne Broome; Hyman, Paul; Bell, Olga; Balmain, Allan; Brown, Ken; Alberts, D S; Bowden, G. Tim

doi:10.1002/mc.2940120205

Cited by 77 publications

(59 citation statements)

References 21 publications

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“…However, both activation and inhibition of ERK signaling can cause increased pigmentation. For example, although melanogenesis in melanocytes is suppressed both in vitro and in vivo by exogenous expression of Ras oncogene (Dotto et al, 1989;Tsukamoto et al, 1992;Wilson et al, 1989), transgenic mice expressing Ras under a mouse tyrosinase promoter demonstrated hyperpigmentation and melanocytic hyperplasia (Powell et al, 1995). Activation of ERK signaling by the c-Kit receptor plays a crucial role in the differentiation of pigment cells during development (Lassam & Bickford, 1992), whereas constitutive ERK signaling in melanoma cells is inhibitory to melanogenesis and inhibition of intrinsic ERK signaling in melanoma cells causes induction of melanogenesis and cellular differentiation (Englaro et al, 1998;Kim et al, 2004).…”

Section: Functional Interaction Of Braf and Ink4a Lesions In Melanomamentioning

confidence: 99%

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Dong¹,

Chet²

2011

Treatment of Metastatic Melanoma

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Section: Functional Interaction Of Braf and Ink4a Lesions In Melanomamentioning

confidence: 99%

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Dong¹,

Chet²

2011

Treatment of Metastatic Melanoma

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“…For example, although melanogenesis in melanocytes is suppressed both in vitro and in vivo by exogenous expression of Ras oncogene, [44][45][46] trans- genic mice expressing Ras under a mouse tyrosinase promoter demonstrated hyperpigmentation and melanocytic hyperplasia. 47 Activation of ERK signaling by the c-Kit receptor plays a crucial role in the differentiation of pigment cells during development, 48 whereas constitutive ERK signaling in melanoma cells could be inhibitory to melanogenesis. 42,43 Although our results demonstrate a melanogenic effect by inhibiting mutant BRAF, it is worth noting that activating BRAF mutations have been found in 70-80% of benign nevi that are dark in color, and some malignant melanomas that are highly pigmented may have BRAF mutation.…”

Section: Ink4amentioning

confidence: 99%

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Rotolo

Diotti

Gordon

et al. 2005

Intl Journal of Cancer

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Activating BRAF mutations and loss of wild-type INK4A expression both occur at high frequencies in melanomas. Here, we present evidence that BRAF and INK4A have different effects on melanogenesis, a marker of melanocytic differentiation. Human melanoma cell line 624Mel harbors mutations in both BRAF and INK4A. The in vitro and in vivo growth of these cells was inhibited by either reduced expression of mutant BRAF using stable retroviral RNA interference (RNAi) or retrovirus-mediated stable expression of wild-type INK4A cDNA. Consistent with the observed growth inhibition, phosphorylation of S780 and S795 in pRB, both CDK4/6 targets, was suppressed in cells expressing either mutant BRAF RNAi or wild-type INK4A. Interestingly, melanoma cells expressing mutant BRAF RNAi had increased pigmentation, produced more mature melanosomes and melanin and expressed higher levels of tyrosinase and tyrosinase-related protein-1, whereas melanogenesis was not induced by wild-type INK4A. We found that the melanocyte lineage-specific master control protein microphthalmia-associated transcription factor was upregulated by inhibition of mutant BRAF, which may be the cause for the melanogenic effect of BRAF RNAi. The results suggest that, although both BRAF and INK4A lesions promote cell growth and tumor formation, mutant BRAF may also induce dedifferentiation in melanoma cells. ' 2005 Wiley-Liss, Inc. Key words:T1796A BRAF; INK4A; melanogenesis; differentiation; melanoma Melanoma is becoming one of the most prevalent malignancies with a dismal prognosis. Further understanding of melanoma biology is required to design better strategies in the treatment of this devastating disease. BRAF mutations have been identified in 70% of human malignant melanomas.1 A T1796A transversion in axon 15, resulting in a V599E substitution in the BRAF kinase domain, accounts for >90% of BRAF mutations detected in melanoma samples.1 BRAF is a component of the RAS-RAF-MEK-ERK signaling pathway that plays essential roles in cell proliferation, differentiation and survival.2 BRAF is one of 3 members of the RAF family, 2 which are serine/threonine kinases that transduce regulatory signals from RAS through MEK to ERK.V599E BRAF has increased kinase activity; causes intrinsic ERK activation in cultured NIH3T3 cells, COS cells and human melanocytes; and leads to elevated transforming activity of cultured NIH3T3 cells and human melanocytes.1,3-5 Suppression of V599E BRAF expression has been reported to cause inhibition of melanoma cell proliferation and survival in vitro and in vivo. 6-8Apart from BRAF mutation, most melanoma cells have lost expression of wild-type INK4A, through either DNA deletion/mutation or promoter hypermethylation.9-12 INK4A encodes the cell cycle regulator p16INK4A , which binds to and inhibits CDK4/6 and promotes cell cycle arrest via the RB tumor-suppressor pathway.13,14 Consistent with a tumor-suppressor role of INK4A in melanomas, a germline R24C mutation in CDK4 has been identified in familial melanoma patients. 15,16 This mutation ...

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“…Transgenic mice that express a mutant form of H-ras specifically in melanocytes showed melanocytic hyperplasia with intense skin pigmentation (9), which after treatment with carcinogens progressed into skin melanoma with metastasis formation in lymph nodes and lung (10). Breeding of Tyr::H-Ras V12G transgenic mice on an INK4a/ARF-or p53-deficient background resulted in the development of highly vascularized but amelanotic melanomas resembling nodular melanoma (11,12).…”

Section: Introductionmentioning

confidence: 99%

Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background

Ackermann¹,

Frutschi²,

Kaloulis³

et al. 2005

Cancer Research

269

303

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Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 HA‐ras gene regulated by a mouse tyrosinase promoter

Cited by 77 publications

References 21 publications

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background

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