Retinoblastoma-associated protein

RB1 (RB1 stands for retinoblastoma protein) is a nuclear regulatory protein encoded by the RB1 gene, which is located on chromosome 13 at the 13q14.2 locus. As a tumor suppressor, pRb ensures that cells do not divide uncontrollably.

The RB1 protein is a nuclear, phosphoregulatory tumor suppressor protein that, as a central regulatory factor of the eukaryotic cell cycle, regulates the transition from the G1 phase to the S phase. It acts as a molecular interface between mitogenic growth signals, transcriptional control, and DNA replication. Its most important function is the binding to and functional inhibition of transcription factors of the E2F family. Loss of its function leads to uncontrolled cell cycle progression and promotes tumor development.

The retinoblastoma protein is involved in cell cycle control. It inhibits the cell’s transition from the G1 phase to the S phase (DNA replication) by binding to and inhibiting transcription factors (such as E2F). When the cell is ready to grow, the pRb protein is phosphorylated and releases the brake (see also the RB1/E2F regulatory axis)

Structure: A characteristic feature is the so-called pocket domain, consisting of two conserved subdomains (A and B), which form a binding surface for E2F proteins and numerous regulatory proteins. The RB1 protein also possesses an N-terminal domain and a C-terminal region that plays a significant regulatory role. Several serine and threonine residues serve as phosphorylation sites for cyclin-dependent kinases (CDKs).

The central function of the RB1 protein is to make cell division dependent on appropriate proliferation-promoting signals.In this process, RB1 does not act as an enzymatically active cell cycle regulator, but rather as a protein-protein interaction platform that links transcription factors and chromatin-modifying protein complexes.

RB1 inactivation: The loss of function of the RB1 protein leads to the uninhibition of E2F-dependent transcription programs and promotes uncontrolled cell proliferation.

Broadly speaking, three mechanisms can be distinguished:

1. Genetic inactivation: Biallelic mutations or deletions of the RB1 gene.
2. Functional inactivation: Excessive CDK activity with dysregulated RB1 phosphorylation, for example, as a result of cyclin D overexpression or loss of CDKN2A/p16.
3. Viral inactivation: Binding of viral oncoproteins to RB1, thereby neutralizing its tumor-suppressive function.

Bone and Soft Tissue Tumors (Sarcomas): People with a congenital RB1 mutation have a significantly increased risk of developing secondary tumors over the course of their lives, particularly osteosarcomas (bone cancer) and soft tissue sarcomas.

Small-cell lung cancer (SCLC): Somatic RB1 mutations are very common in aggressive forms of lung cancer, particularly in small-cell lung cancer (SCLC).

Bladder cancer and breast cancer: A loss of function in the gene is regularly detected in bladder carcinomas as well as in certain forms of breast cancer (e.g., triple-negative breast cancer).

Other tumor types: Alterations in the RB1 gene also play a role in melanomas, pineoblastomas (often in the context of what is known as a trilateral retinoblastoma), gliomas, and certain leukemias.

The Merkel cell polyomavirus (MCPyV) expresses a large T antigen (LT) that possesses a conserved LxCxE-binding sequence. Through this motif, the viral protein interacts with the pocket domain of the RB1 protein.

It is noteworthy that the Large-T antigen expressed in Merkel cell carcinomas is typically truncated at the C-terminus. As a result, the domains required for viral DNA replication are lost, while the RB1 binding site is preserved.

Therapeutic Significance

The RB1 signaling pathway is an important target for targeted cancer therapies.

CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—reduce CDK4/6-mediated RB1 phosphorylation and can thereby preserve the tumor-suppressive function of pRB.

A prerequisite for this mechanism of action is a functionally sufficient amount of RB1 protein. In cases of complete RB1 loss, the efficacy of isolated CDK4/6 inhibition is often limited.

To date, there is no clinically established therapy specifically targeting RB1 inactivation in Merkel cell carcinoma.

1. Berry JL et al. (2019) The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene. Genes (Basel) 10(11):879.
2. Dimaras H et al. (2015) Retinoblastoma. Nat Rev Dis Primers 1:15021.
3. Indovina P et al. (2019) Translating the predictive value of RB1 into clinical cancer therapy: Are we there yet? Biochem Pharmacol 166:323–334.
4. Knudsen ES et al. (2020) Pan-cancer molecular analysis of the RB tumor suppressor pathway. Commun Biol 3:158.