Tumor Suppressor miR-22 Determines p53-Dependent Cellular Fate through Post-transcriptional Regulation of p21

Abstract

Selective activation of p53 target genes in response to various cellular stresses is a critical step in determining the ability to induce cell-cycle arrest or apoptosis. Here we report the identification of the microRNA miR-22 as a p53 target gene that selectively determines the induction of p53-dependent apoptosis by repressing p21. Combinatorial analyses of the AGO2 immunocomplex and gene expression profiles identified p21 as a direct target of miR-22. Induction of p21 was inhibited by miR-22 after exposure to the genotoxic agent Adriamycin (doxorubicin; Bedford Laboratories), sensitizing cells to p53-dependent apoptosis. Interestingly, the activation of miR-22 depended on the intensity of the stresses that induced cells to undergo apoptosis in the presence of p21 suppression. Our findings define an intrinsic molecular switch that determines p53-dependent cellular fate through post-transcriptional regulation of p21. Cancer Res; 71(13); 4628-39. Ó2011 AACR.

MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1

“…Several studies have proposed that miR-22 is a tumor suppressor because it induces senescence-like phenotypes in cancer cells and it triggers both growth suppression and apoptosis (21,(28)(29)(30)(31). However, our data highlight an oncogenic function of miR-22, in which it inhibits DSB repair and consequently increases the risk of genomic instability, a hallmark of cancer cells.…”

“…Hence, cellular senescence is a potent tumor-suppressing mechanism, but at the same time, it also contributes to cancer promotion at an advanced age (46). miR-22 has been proposed to be a tumor suppressor because it could inhibit cell proliferation and induce a senescence-like phenotype in human breast, cervical, and colon cancer cells (21,28,31). However, it was also proposed that miR-22 had oncogenic functions because it targets ten eleven translocation (TET) tumor suppressors in breast cancer cells and hematopoietic stem cells (47,48).…”

A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis

“…The in vitro and in vivo CD147 rescue experiments proved that miR-22 regulated invasion and metastasis of breast cancer cells mainly by targeting CD147. miR-22 plays a tumorsuppressive role by downregulating oncogenic target genes in many kinds of cancer, including breast cancer (18,19,21,45). However, on the other side, miR-22 was recently suggested to have an oncogenic role by targeting PTEN or TET family (16,46).…”

“…We have identified that miR-22 is downregulated in gastric cancer and its overexpression inhibits cell migration and invasion (15). Lately, several targets of miR-22 have been reported to mediate its tumor-suppressive effect, such as tumor-suppressive PTEN, Max genes, p21 and oncogene c-Myc expression, etc (14)(15)(16)(17)(18). In breast cancer cells, miR-22 might act as a tumor suppressor to repress cancer metastasis and progression by either downregulating EVI-1 oncogene expression and the estrogen signaling pathway or inducing cellular senescence (19)(20)(21).…”

A microRNA signature specific for hairy cell leukemia and associated with modulation of the MAPK–JNK pathways

“…The CDKN1A (p21) protein has been recently reported to be regulated by miR-22, whose overexpression in HCL could contribute to make HCL cells more resistant to apoptosis. 12 To gain further insights on the potential role of miRNAs in HCL pathogenesis, we applied five target prediction algorithms (MiRBase Targets, TargetScan, PicTar, RNA22 and PITA) 13 to identify the candidate targets of the six-miRNA HCL-specific signature. Targets commonly predicted by at least four of the prediction methods and expressed in B cells were further investigated.…”