
-   Regulation of gene CDKN1A gene transcription occurs through p53-dependent and p53-independent pathways [PMID: 25514883]. CDKN1A was identified as a target of p53 through subtractive hybridization in a human brain tumor cell line expressing wild-type p53. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of CDKN1A coding sequences. The CDKN1A promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene [PMID: 8242752].
-   The p53-independent transactivation of CDKN1A by activated Ras requires the transcription factor E2F1. E2F1 and E2F3 strongly activate CDKN1A transcription by binding to cis-acting elements between -119 to +16 of CDKN1A6. Raf, a downstream effector of Ras, also transactivates CDKN1A independently of p53. Besides mitogen-dependent transactivation through the HRAS-Raf-MAPK pathway, CDKN1A transcription is also activated by several nuclear receptors including retinoid receptors, vitamin D receptors and androgen receptors. These operate independently of p53 through binding to their cognate responsive elements in the CDKN1A promoter. The transcription factors SP1, SP3, AP2, CCAAT/enhancer binding protein-alpha (C/EBPalpha), C/EBPbeta, BETA2, GAX, homeobox A10, STATs and myoblast determination protein 1 (mYoD1) also control CDKN1A transcription and upregulate p21 in response to a plethora of stimuli and anticancer agents. Several of the transcriptional inducers of p21, such as nerve growth factor (NGF), progesterone, Ca2+ or the transcription factors BETA2 and mYoD1, cooperate with the transcriptional co-activator p300-CREBBP to activate the CDKN1A promoter [PMID: 19440234].
-   In actively dividing cells, p21 is an unstable protein with a half-life of about 20 to 60 minutes. The protein is protected from proteosomal degradation by WISp39, a tetratricopeptide repeat (TPR) protein. This stabilization occurs through a trimeric complex formation with p21 and Hsp90, where point mutations in WISp39's C-terminal TPR domain disrupt its interaction with Hsp90, leading to a failure in stabilizing p21 [PMID: 15664193].
-   Liver receptor homolog-1 (LRH-1, NR5A2) cooperates with FOXA1 and binds directly to CDKN1A promoter allowing repression of CDKN1A transcription in breast tumor cells. High LRH-1 level is inversely correlated with CDKN1A expression in breast cancer patients and is associated with poor prognosis [PMID: 25435372].
-   CDKN1A was upregulated in mice on a high-fat diet. The upregulation was attenuated if diet was supplemented by lingonberry [PMID: 34835949].
-   RBMS2 inhibited the proliferation of breast cancer and P21 was the main target of RBMS2. RBMS2 stabilized the mRNA of P21 by directly binding to the AU-rich element of 3'-UTR region [PMID: 30514345].
