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Alterations in proteome and proteostasis networks during replicative senescence

ABSTRACT: The accumulation of senescent cells constitutes a pivotal hallmark of tissue ageing, contributing to disruption of tissue homeostasis and thus, to the development of several aging-related diseases. Despite this, our knowledge about the molecular, spatial and temporal changes that drive aging on a cellular basis remains poorly understood. To elucidate these mechanisms, we employed mass spectrometry-based proteomics to determine changes in the total proteome, the ubiquitin-modified proteome, the phospho-proteome and in protein solubility during replicative senescence in human IMR90 fibroblasts. This accession contains the proteome data, across 4 distinct time points, with consecutive increasing concentrations of senescent cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast Of Lung, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Petra Beli

LAB HEAD: Petra Beli

PROVIDER: PXD067595 | Pride | 2026-07-16

REPOSITORIES: Pride

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			Action	DRS
	20220428_SFB1_PBE_WJJ_TMT_IMR90_proteome_GC1_03.raw	Raw
	20220428_SFB1_PBE_WJJ_TMT_IMR90_proteome_GC1_11.raw	Raw
	20220428_SFB1_PBE_WJJ_TMT_IMR90_proteome_GC1_36.raw	Raw
	20220428_SFB1_PBE_WJJ_TMT_IMR90_proteome_GC1_39.raw	Raw
	20220428_SFB1_PBE_WJJ_TMT_IMR90_proteome_GC1_425.raw	Raw

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Project description:Melanocytes within benign human nevi are the paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. These cells typically contain mutations in either the BRAF or N-RAS oncogene and express markers of senescence, including p16. However, a nevus can contain 10s to 100s of thousands of clonal melanocytes and approximately 20-30% of melanoma are thought to arise in association with a pre-existing nevus. Neither observation is indicative of fail-safe senescence-associated proliferation arrest and tumor suppression. We set out to better understand the status of nevus melanocytes. Proliferation-promoting Wnt target genes, such as cyclin D1 and c-myc, were repressed in oncogene-induced senescent melanocytes in vitro, and repression of Wnt signaling in these cells induced a senescent-like state. In contrast, cyclin D1 and c-myc were expressed in many melanocytes of human benign nevi. Specifically, activated Wnt signalling in nevi correlated inversely with nevus maturation, an established dermatopathological correlate of clinical benignancy. Single cell analyses of lone epidermal melanocytes and nevus melanocytes showed that expression of proliferation-promoting Wnt targets correlates with prior proliferative expansion of p16-expressing nevus melanocytes. In a mouse model, activation of Wnt signaling delayed, but did not bypass, senescence of oncogene-expressing melanocytes, leading to massive accumulation of proliferation-arrested, p16-positive non-malignant melanocytes. We conclude that clonal hyperproliferation of oncogene-expressing melanocytes to form a nevus is facilitated by transient delay of senescence due to activated Wnt signaling. The observation that activation of Wnt signaling correlates inversely with nevus maturation, an indicator of clinical benignancy, supports the notion that persistent destabilization of senescence by Wnt signaling contributes to the malignant potential of nevi. We used microarrays to detail the global programme of gene expression after lentiviral infection of BRAF in 3 replicates. Primary human melanocytes were infected/uninfected with lentivirus containing either an Empty Vector or activated BRAFV600E mutant in three biological replicates

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Alterations in proteome and proteostasis networks during replicative senescence

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