Abstract
SRSF1 triggers senescence via stabilization of p53 protein as part of a RPL5–MDM2 complex.
Major finding: SRSF1 triggers senescence via stabilization of p53 protein as part of a RPL5–MDM2 complex.
Mechanism: SRSF1 is necessary to inhibit MDM2-dependent p53 degradation in response to ribosomal stress.
Impact: RPL5–MDM2-mediated p53 regulation restrains the oncogenic effects of SRSF1 overexpression.
Perturbations in ribosome biogenesis or function, including those induced by oncogene activation, trigger a ribosomal stress response pathway mediated by ribosomal proteins (RP) such as RPL5 that modulate the function of the E3 ubiquitin ligase MDM2 and thus promote p53 stabilization and activity. Fregoso and colleagues found that the proto-oncogene serine/arginine-rich splicing factor 1 (SRSF1), which regulates multiple steps in gene expression in addition to splicing and is overexpressed in many cancers, specifically interacted with RPL5 and MDM2. This nuclear complex formed independently of mRNA or the ribosome and was distinct from the canonical RP–MDM2 complex. Actinomycin D-induced ribosomal stress enhanced this interaction and resulted in decreased ubiquitination and reduced degradation of p53 protein in the absence of changes in TP53 transcription, splicing, or mRNA stability and without augmenting p53 translation. Stabilization of p53 in response to ribosomal stress but not DNA damage was dependent on SRSF1 expression and its interaction with RPL5, which was mediated by the RRM1 domain of SRSF1. Consistent with a role for SRSF1 in regulating the p53 pathway, even modest overexpression of SRSF1 diminished the proliferation of nontransformed human fibroblasts and triggered p53-dependent oncogene-induced senescence (OIS) as a barrier to limit oncogenic transformation in these cells. This senescent phenotype was not associated with stimulation of the DNA damage response or p14/ARF, unlike OIS activated by other oncoproteins such as RAS. Moreover, elevated SRSF1 expression in human kidney, colon, and breast cancers was inversely correlated with TP53 expression, supporting the idea that inactivation of the p53 pathway is necessary to overcome OIS in SRSF1-overexpressing cells. These results identify a noncanonical, autoregulatory function of SRSF1 and implicate the ribosomal stress pathway as an important regulator of OIS.
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