Regulating tumor suppressor genes: post-translational modifications

Abstract

Tumor suppressor genes cooperate with each other in tumors. Three important tumor suppressor proteins, retinoblastoma (Rb), p53, phosphatase, and tensin homolog deleted on chromosome ten (PTEN) are functionally associated and they regulated by post-translational modification (PTMs) as well. PTMs include phosphorylation, SUMOylation, acetylation, and other novel modifications becoming growing appreciated. Because most of PTMs are reversible, normal cells use them as a switch to control the state of cells being the resting or proliferating, and PTMs also involve in cell survival and cell cycle, which may lead to abnormal proliferation and tumorigenesis. Although a lot of studies focus on the importance of each kind of PTM, further discoveries shows that tumor suppressor genes (TSGs) form a complex "network" by the interaction of modification. Recently, there are several promising strategies for TSGs for they change more frequently than carcinogenic genes in cancers. We here review the necessity, characteristics, and mechanisms of each kind of post-translational modification on Rb, p53, PTEN, and its influence on the precise and selective function. We also discuss the current antitumoral therapies of Rb, p53 and PTEN as predictive, prognostic, and therapeutic target in cancer.

Fig. 1

Rb structural domains. Rb structured domains include the N-terminal domain (RbN), the pocket domain, and parts of the C-terminal domain (RbC)

Fig. 2

The Rb canonical and non-canonical pathways. Signals of growth factors, DNA damage, and transforming growth factor-β (TGFβ) activate CDKs to phosphorylate and inactivate Rb, whereas CDK inhibitors activates Rb. Inactivation of Rb in the canonical pathway results in transcription of E2F target genes; Stresses and DNA damage stimulates acetylation and methylation of Rb, which can maintain genomic stability by locating DNA break sites and stimulating non-homologous end connections or homologous recombination repair. Rb also recruits enhancers from EZH2 to H3K27me3 to ensure the fidelity of DNA replication and chromosome aggregation

Fig. 3

Ubiquitinated and de-ubiquitinated p53 functions and pathways. p53 is degraded after MDM2-mediated ubiquitination, and other DUBs stabilize p53 by eliminating ubiquitin from p53. Under normal conditions, MDM2, a target of p53, inhibits p53 activity by forming a p53/MDM2 auto-regulatory feedback loop. Furthermore, MDM2 can bind to p53 and control p53 monoubiquitination, leading to the nuclear export of p53. Other E3 ligases further promote p53 poly-ubiquitination and 26S proteasomal degradation in the cytoplasm. Upon DNA damage, DUBs localize to the nucleus and de-ubiquitinate p53 to alter its stability, thus boosting p53 activation. Consequently, p53 is activated through various kinase or acetyltransferases, after which it binds to its transcriptional targets, including p21, p53 upregulated modulator of apoptosis (PUMA), Bax and Noxa, for example. Ub ubiquitin, DUBs de-ubiquitinating enzymes

Fig. 4

Autoregulatory loop of p53 and MDM2. The RING finger domain of MDM2 is involved in p53 ubiquitination and proteasome-mediated degradation, and, therefore, MDM2 maintains appropriately low p53 levels under unstressed conditions. Activated p53 transcribes MDM2 mRNA and increases the level of MDM2 protein, which in turn reduces p53 activity

Fig. 5

p53 structural domains and sites for post-transcriptional modifications. More than 36 amino acids of p53 are reported to be modified. The major sites of p53 post-transcriptional modification are shown with the corresponding main modifying enzymes. The modifications directly responsible for the listed effects are shown. M methylation, A acetylation, U ubiquitination, S sumoylation, P phosphorylation. CK1 casein kinase 1, Chk2 checkpoint kinase 2, ATM ataxia telangiectasia, mutated, hMOF human males absent on the first, MOZ monocytic leukemia zinc-finger protein, TIP60 HIV1-TAT interactive protein, HIPK2 homeodomain interacting protein kinase-2, JNK c-Jun amino terminal kinase, CDK2 cell cycle control regulator cyclin-dependent kinase-2, PCAF p300/CBP-associated factor, PRMT protein arginine methyltransferase, L3MBTL1 lethal 3 malignant brain tumor-like 1, SIM mortality information system, PKR double-stranded RNA-dependent protein kinase

Fig. 6

PTEN structural domains and sites for phosphorylation. PTEN structured domains include the PIP2 binding domain, phosphatase domain, two C-terminal domains, and PDZ domain. PIP2 phosphatidylinositol diphosphate, PDZ post-synaptic95, disks large, zonula occludens, CK2 casein kinase 2, GSK3β glycogen synthase kinase-3β, LKB1 liver kinase B1, PICT1 protein interacting with carboxyl terminus 1, PLK1 polo-like kinase 1, PTEN phosphatase and tensin homolog, ROCK rhoA-associated protein kinase, Ser serine, Thr threonine, Tyr tyrosine

Fig. 7

Response of cell stress on regulation of p53 function by Rb and PTEN. a The response of cells to stress is phosphorylation of Rb, and the stabilization of the p53 protein. Such stabilization readies the cell for an apoptosis. b One of the target genes activated by p53 is MDM2. Nuclear entry of MDM2 blocks p53 transactivation and promotes p53 degradation. c p53 activates the gene encoding PTEN. PTEN protein inhibits PI3K signaling and increases cellular levels of p53. Induction of PTEN by p53 could enhance p53 function and activate apoptotic response of cells

Fig. 8

Interplay among post-translational modifications (PTMs) in the regulation of disease. Five main PTMs (phosphorylation, ubiquitination, acetylation, sumoylation and glycosylation) as well as their relative reverse processes (dephosphorylation, deubiquitination, and deacetylation) are involved in the regulation of cancer. In conclusion, the balance of cell (Yin–Yang; Yin, black; Yang, white) is crucial for maintaining cell fundamental functions, whereas dysfunction is associated with normal aging as well as with many human diseases including premature aging diseases, cancer, heart failure, autoimmune disease, and neurodegenerative disease