SOCS1: phosphorylation, dimerization and tumor suppression.

Suppressor of cytokine signaling (SOCS) family members are upregulated following JAK-STAT pathway activation by cytokines. SOCS proteins are recognized inhibitors of cytokine signaling playing roles in cell growth and differentiation. Moreover, SOCS1 and SOCS3 have been shown to be involved in tumor suppression through their ability to interact with p53 leading to the activation of its transcriptional program and showing the implication of SOCS family members in the regulation of apoptosis, ferroptosis and senescence.

Phosphorylation of SOCS1 Inhibits the SOCS1-p53 Tumor Suppressor Axis.

Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1.

Ribosomal protein RPL22/eL22 regulates the cell cycle by acting as an inhibitor of the CDK4-cyclin D complex.

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).

The senescence-associated secretory phenotype and its regulation.

The senescence-associated secretory phenotype (SASP) defines the ability of senescent cells to express and secrete a variety of extracellular modulators that includes cytokines, chemokines, proteases, growth factors and bioactive lipids. The role of the SASP depends on the context. The SASP reinforces the senescent cell cycle arrest, stimulates the immune-mediated clearance of potentially tumorigenic cells, limits fibrosis and promotes wound healing and tissue regeneration.

Circumventing senescence is associated with stem cell properties and metformin sensitivity.

Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity).

Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway.

Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence.

SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes.

The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition.

Sponges against miR-19 and miR-155 reactivate the p53-Socs1 axis in hematopoietic cancers.

Normal cell proliferation is controlled by a balance between signals that promote or halt cell proliferation. Micro RNAs are emerging as key elements in providing fine signal balance in different physiological situations. Here we report that STAT5 signaling induces the miRNAs miR-19 and miR-155, which potentially antagonize the tumor suppressor axis composed by the STAT5 target gene SOCS1 (suppressor of cytokine signaling-1) and its downstream effector p53.

CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis.

The expression of the forkhead transcription factor checkpoint suppressor 1 (CHES1), also known as FOXN3, is reduced in many types of cancers. We show here that CHES1 decreases protein synthesis and cell proliferation in tumor cell lines but not in normal fibroblasts. Conversely, short hairpin RNA-mediated depletion of CHES1 increases tumor cell proliferation.