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Senescence is a tumor suppressor program characterized by a stable growth arrest while maintaining cell viability. Senescence-associated ribogenesis defects (SARD) have been shown to regulate senescence through the ability of the ribosomal protein S14 (RPS14 or uS11) to bind and inhibit the cyclin-dependent kinase 4 (CDK4). Here we report another ribosomal protein that binds and inhibits CDK4 in senescent cells: L22 (RPL22 or eL22). Enforcing the expression of RPL22/eL22 is sufficient to induce an RB and p53-dependent cellular senescent phenotype in human fibroblasts. Mechanistically, RPL22/eL22 can interact with and inhibit CDK4-Cyclin D1 to decrease RB phosphorylation both in vitro and in cells. Briefly, we show that ribosome-free RPL22/eL22 causes a cell cycle arrest which could be relevant during situations of nucleolar stress such as cellular senescence or the response to cancer chemotherapy.

The Christmas tree view of active ribosomal RNA (rRNA) genes suggests a gene topology in which a large number of nascent rRNA transcripts are prevented from intertwining. The way in which this is achieved has remained unclear. By using a combination of chromatin immunoprecipitation and chromosome conformation capture techniques, we show that the promoter, upstream region and terminator R3 of active rRNA genes are held together spatially throughout the cell cycle, forming a stable core around which the transcribed region is organized. We suggest a new core-helix model for the topology of rRNA genes, that provides a structural basis for the productive synthesis or rRNA.

Constitutive nuclear factor κB (NF-κB) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-κB signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-κB and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy. • NFE2L3 levels are elevated in colon cancer patients • NFE2L3 expression is regulated by the RELA subunit of NF-κB • Silencing of NFE2L3 decreases colon cancer cell proliferation • NFE2L3 acts as a repressor of DUX4, a direct inhibitor of CDK1 activity Bury et al. show that the expression of the transcription factor NFE2L3 is regulated by NF-κB and that NFE2L3 levels are elevated in colon cancer patients. Knockdown of NFE2L3 inhibits colon cancer cell proliferation through induction of DUX4, a direct inhibitor of CDK1, establishing a pathway governing colon tumor growth. [ABSTRACT FROM AUTHOR]

Cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), control the transition between different phases of the cell cycle. CDK/cyclin activity is regulated by CDK inhibitors (CKIs), currently comprising the CDK-interacting protein/kinase inhibitory protein (CIP/KIP) family and the inhibitor of kinase (INK) family. Recent studies have identified a third group of CKIs, called ribosomal protein-inhibiting CDKs (RPICs). RPICs were discovered in the context of cellular senescence, a stable cell cycle arrest with tumor-suppressing abilities. RPICs accumulate in the nonribosomal fraction of senescent cells due to a decrease in rRNA biogenesis. Accordingly, RPICs are often downregulated in human cancers together with other ribosomal proteins, the tumor-suppressor functions of which are still under study. In this review, we discuss unique therapies that have been developed to target CDK activity in the context of cancer treatment or senescence-associated pathologies, providing novel tools for precision medicine. The cell cycle is a complex process that is controlled by multiple regulatory pathways that also integrate extracellular signals to govern cell growth and division. Ribosomal proteins are key regulators of the cell cycle. Recent research studies confirmed the existence of a third class of cyclin-dependent kinase (CDK) inhibitors, besides CDK-interacting protein/kinase inhibitory protein (CIP/KIP) and inhibitor of kinase (INK) families, called ribosomal protein inhibiting CDKs (RPICs). The new cell cycle regulators constitute valuable targets for precision medicine, through the identification of peptides or small molecules mimicking their CDK inhibitor activities, opening novel avenues for the treatment of cancer and aging-related diseases. [ABSTRACT FROM AUTHOR]

Constitutive activation of growth factor signaling pathways paradoxically triggers a cell cycle arrest known as cellular senescence. Inrimary cells expressing oncogenic ras, this mechanism effectively prevents cell transformation. Surprisingly, attenuation of ERK/MAPinase signaling by genetic inactivation of Erk2, RNAi-mediated knockdown of ERK1 or ERK2, or MEK inhibitors prevented thectivation of the senescence mechanism, allowing oncogenic ras to transform primary cells. Mechanistically, ERK-mediatedenescence involved the proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions,ell migration, RNA metabolism, and cell signaling. This senescence-associated protein degradation (SAPD) was observed not only n cells expressing ectopic ras, but also in cells that senesced due to short telomeres. Individual RNAi-mediated inactivation of SAPD targets was sufficient to restore senescence in cells transformed by oncogenic ras or trigger senescence in normal cells. Conversely, the anti-senescence viral oncoproteins E1A, E6, and E7 prevented SAPD. In human prostate neoplasms, high levels of hosphorylated ERK were found in benign lesions, correlating with other senescence markers and low levels of STAT3, one of the APD targets. We thus identified a mechanism that links aberrant activation of growth signaling pathways and short telomeres torotein degradation and cellular senescence. [ABSTRACT FROM AUTHOR]