MC1R Is a potent regulator of PTEN after UV exposure in melanocytes

Juxiang Cao; Lixin Wan; Elke Hacker; Xiangpeng Dai; Stefania Lenna; Celia Jimenez-Cervantes; Yongjun Wang; Nick R Leslie; George X. Xu; Hans R. Widlund; Byungwoo Ryu; Rhoda M. Alani; Ken Dutton-Regester; Colin R. Goding; Nicholas K. Hayward; Wenyi Wei; Rutao Cui

doi:10.1016/j.molcel.2013.08.010

MC1R Is a potent regulator of PTEN after UV exposure in melanocytes

Juxiang Cao, Lixin Wan, Elke Hacker, Xiangpeng Dai, Stefania Lenna, Celia Jimenez-Cervantes, Yongjun Wang, Nick R Leslie, George X. Xu, Hans R. Widlund, Byungwoo Ryu, Rhoda M. Alani, Ken Dutton-Regester, Colin R. Goding, Nicholas K. Hayward, Wenyi Wei, Rutao Cui

Research output: Contribution to journal › Article › peer-review

99 Citations (Scopus)

Abstract

The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wildtype (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyper-activation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.

Original language	English
Pages (from-to)	409-422
Number of pages	14
Journal	Molecular Cell
Volume	51
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2013.08.010
Publication status	Published - 22 Aug 2013

Keywords

ONCOGENE-INDUCED SENESCENCE
BRAF-MUTANT MELANOMA
CELLULAR SENESCENCE
MALIGNANT-MELANOMA
TUMOR-SUPPRESSOR
RED HAIR
VARIANTS
KERATINOCYTES
ACTIVATION
MECHANISMS

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10.1016/j.molcel.2013.08.010

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Cao, J., Wan, L., Hacker, E., Dai, X., Lenna, S., Jimenez-Cervantes, C., Wang, Y., Leslie, N. R., Xu, G. X., Widlund, H. R., Ryu, B., Alani, R. M., Dutton-Regester, K., Goding, C. R., Hayward, N. K., Wei, W., & Cui, R. (2013). MC1R Is a potent regulator of PTEN after UV exposure in melanocytes. Molecular Cell, 51(4), 409-422. https://doi.org/10.1016/j.molcel.2013.08.010

Cao, Juxiang ; Wan, Lixin ; Hacker, Elke ; Dai, Xiangpeng ; Lenna, Stefania ; Jimenez-Cervantes, Celia ; Wang, Yongjun ; Leslie, Nick R ; Xu, George X. ; Widlund, Hans R. ; Ryu, Byungwoo ; Alani, Rhoda M. ; Dutton-Regester, Ken ; Goding, Colin R. ; Hayward, Nicholas K. ; Wei, Wenyi ; Cui, Rutao. / MC1R Is a potent regulator of PTEN after UV exposure in melanocytes. In: Molecular Cell. 2013 ; Vol. 51, No. 4. pp. 409-422.

@article{3a82492c8b7e40138fe968c4a43fad69,

title = "MC1R Is a potent regulator of PTEN after UV exposure in melanocytes",

abstract = "The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wildtype (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyper-activation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.",

keywords = "ONCOGENE-INDUCED SENESCENCE, BRAF-MUTANT MELANOMA, CELLULAR SENESCENCE, MALIGNANT-MELANOMA, TUMOR-SUPPRESSOR, RED HAIR, VARIANTS, KERATINOCYTES, ACTIVATION, MECHANISMS",

author = "Juxiang Cao and Lixin Wan and Elke Hacker and Xiangpeng Dai and Stefania Lenna and Celia Jimenez-Cervantes and Yongjun Wang and Leslie, {Nick R} and Xu, {George X.} and Widlund, {Hans R.} and Byungwoo Ryu and Alani, {Rhoda M.} and Ken Dutton-Regester and Goding, {Colin R.} and Hayward, {Nicholas K.} and Wenyi Wei and Rutao Cui",

year = "2013",

month = aug,

day = "22",

doi = "10.1016/j.molcel.2013.08.010",

language = "English",

volume = "51",

pages = "409--422",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "4",

}

MC1R Is a potent regulator of PTEN after UV exposure in melanocytes. / Cao, Juxiang; Wan, Lixin; Hacker, Elke; Dai, Xiangpeng; Lenna, Stefania; Jimenez-Cervantes, Celia; Wang, Yongjun; Leslie, Nick R; Xu, George X.; Widlund, Hans R.; Ryu, Byungwoo; Alani, Rhoda M.; Dutton-Regester, Ken; Goding, Colin R.; Hayward, Nicholas K.; Wei, Wenyi; Cui, Rutao.

In: Molecular Cell, Vol. 51, No. 4, 22.08.2013, p. 409-422.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - MC1R Is a potent regulator of PTEN after UV exposure in melanocytes

AU - Cao, Juxiang

AU - Wan, Lixin

AU - Hacker, Elke

AU - Dai, Xiangpeng

AU - Lenna, Stefania

AU - Jimenez-Cervantes, Celia

AU - Wang, Yongjun

AU - Leslie, Nick R

AU - Xu, George X.

AU - Widlund, Hans R.

AU - Ryu, Byungwoo

AU - Alani, Rhoda M.

AU - Dutton-Regester, Ken

AU - Goding, Colin R.

AU - Hayward, Nicholas K.

AU - Wei, Wenyi

AU - Cui, Rutao

PY - 2013/8/22

Y1 - 2013/8/22

N2 - The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wildtype (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyper-activation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.

AB - The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wildtype (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyper-activation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.

KW - ONCOGENE-INDUCED SENESCENCE

KW - BRAF-MUTANT MELANOMA

KW - CELLULAR SENESCENCE

KW - MALIGNANT-MELANOMA

KW - TUMOR-SUPPRESSOR

KW - RED HAIR

KW - VARIANTS

KW - KERATINOCYTES

KW - ACTIVATION

KW - MECHANISMS

U2 - 10.1016/j.molcel.2013.08.010

DO - 10.1016/j.molcel.2013.08.010

M3 - Article

C2 - 23973372

VL - 51

SP - 409

EP - 422

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 4

ER -

MC1R Is a potent regulator of PTEN after UV exposure in melanocytes

Abstract

Keywords

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