Id1 delays senescence of primary human melanocytes

Abstract

The Id family of helix-loop-helix transcription factors is upregulated in a variety of human malignancies and has been implicated in promoting tumorigenesis through effects on cell growth, differentiation, and tumor angiogenesis. While expression of Id proteins has been associated with tumorigenesis, the precise mechanistic relationship between Id expression and carcinogenesis has not been clearly delineated. We have previously shown that Id1 delays cellular senescence in primary mammalian cells through inhibition of the cell cycle regulatory protein and familial melanoma gene, p16/INK4a. We have also demonstrated that Id1 expression is upregulated in early stage primary human melanomas and may be an important marker for early malignancy. In order to further define the role of Id1 in human melanoma development, we have evaluated the function of Id1 in primary human melanocytes. Here we show that constitutive expression of Id1 in primary human melanocytes leads to delayed cellular senescence and decreased expression of the familial melanoma gene, p16/INK4a. Although melanocytes constitutively expressing Id1 are shown to possess extended lifespans, this is not associated with an appreciable change in cell growth or telomere length. We conclude that Id1 delays cellular senescence in primary human melanocytes through inhibition of p16/INK4a expression and suggest that Id1 may contribute to the malignant conversion of primary human melanocytes through extension of cellular lifespan.

Smurf2‐mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence

“…Consistent with this notion, Id1 is found to suppress p16 expression through its ability to sequester bHLH transcription factor E47 and prevent E47 from transactivating p16 (Alani et al 2001; Zheng et al 2004). Down-regulation of Id1 has been found to activate senescence and p16 expression (Alani et al 2001; Zheng et al 2004), whereas ectopic expression of Id1 delays senescence in human and mouse cells (Hara et al 1996; Nickoloff et al 2000; Tang et al 2002; Cummings et al 2008; Suh et al 2008), suggesting that Id1 plays a critical role in replicative senescence. In addition, Id1 is implicated in regulating p16 expression during stress-induced senescence.…”

Evidence ofγ-Tocotrienol as an Apoptosis-Inducing, Invasion-Suppressing, and Chemotherapy Drug-Sensitizing Agent in Human Melanoma Cells

“…Previously, skin melanocytes that constitutively were expressing Id-1 were shown to delay cellular senescence that is not associated with a change in cell growth or telomere length(36). In addition, it was also determined that elevated Id-1 protein levels were present consistently in radial growth phase melanomas, suggesting its role in initiation of carcinogenesis in melanoma(37).…”

Id1 overexpression is independent of repression and epigenetic silencing of tumor suppressor genes in melanoma

“…Since Id1 has been reported to regulate the G 1 /S cell cycle transition and Id1 overexpression delays senescence in melanocytes, 11 we examined Id1-associated changes in growth rate and cell cycle distribution. Id1 overexpression correlated with a slight decrease in doubling time, but this difference was not statistically significant (2.13 ± 0.27 ID1 versus 2.22 ± 0.28 GFP mock MOI 10 in WM902B, p = 0.8284; 2.06 ± 0.30 ID1 versus 2.20 ± 0.10 GFP mock MOI 10 in WM983A, p = 0.6809, unpaired t test, Supp 1A and B).…”

“…9,10 In a human melanocyte model, Id1 overexpression appeared to delay senescence by downregulating p16, 11 although it is unclear whether Id overexpression is an obligate event for melanomagenesis and when repression of p16 might transition to epigenetic inactivation.…”