Catálogo de publicaciones - libros

RB plays an essential role in epithelial cell differentiation and viability, these two properties being totally linked and independent of p53. To exert these functions, RB acts as a positive transcriptional coregulator, being recruited to the native gene promoters by sequence-specific transcription factors such as AP-2, thus implying direct activation of the target genes, rather than the downregulation of a repressor. Physical and functional interactions have been shown to exist in vivo between RB and transcription factors such as AP-1, AP-2 and SP1 family members, and a number of RB target genes that are specifically activated by RB in epithelial cells have been identified, including c-jun, collagenase, E-cadherin, p21 and Bcl-2. It is likely that other proteins are also associated with the RB/transcription factor protein complexes — in particular, proteins with histone acetyltransferase (HAT) activity, because gene promoters were found to be specifically acetylated when RB and AP-2 bound to them. Since comparable results have been reported for an osteoblast differentiation model, it seems likely that this mechanism might constitute a new paradigm for RB action in several differentiation systems. The mechanism of interaction of RB with viral oncoproteins seems to be different when it acts as a positive regulator versus a negative regulator. In differentated epithelial cells, the RB trancription factor complex is not dissociated by oncoprotein such as SV40LT, but rather a tripartite complex is formed containing the oncoprotein.

This chapter deals with the role played by the retinoblastoma protein (pRb) in a variety of differentiation processes. After broadly reviewing the current knowledge on this issue, it points at two common themes. The first is the exclusive involvement of pRb in the final maturation stages of each lineage, so that the functional ablation of the protein produces relatively subtle differentiation defects. The second is that, at least in the cell types more thoroughly investigated, pRb exerts its pro-differentiation potential by enhancing the activities of transcription factors that are key regulators of tissue-specific differentiation.

Finally, the hypothesis is put forward that pRb plays a role in the final differentiation stages of a much wider range of cell types than currently recognized. It is proposed that one reason for the well-know, poorly-understood, inverse relationship between differentiation and malignancy is the functional impairment of pRb and possibly its family members in the vast majority of human cancers.

RB is a critical tumor suppressor targeted at high frequency in human cancers. As part of its mode of action RB participates in the regulation of DNA replication. In the absence of functional RB aberrant replication cycles occur and genotoxic stresses are compromised for inhibiting of DNA replication. Varied mechanisms through which RB inhibits S-phase have been described and provide evidence for temporally regulated stalling of replication initiation followed by a stable replicative exit.

The retinoblastoma (Rb) protein is a key regulator of cell proliferation, differentiation, and tumorigenesis. Initial studies of Rb revealed that it binds to, and decreases the activity of, the E2F family of transcription factors. Over the last decade, the mechanisms by which Rb regulates E2F activity have been well-studied. These investigations have lead to a commonly held belief that Rb functions solely as a transcriptional repressor. However, although not as commonly discussed, there are many examples of Rb synergizing with site-specific transcription factors to activate transcription. This Rb-mediated activation appears to be cell type-specific, transcription factor-specific, and even promoter-specific. This chapter details some of the examples of Rb-mediated transcriptional activation and suggests future studies that could provide insight into the mechanisms by which Rb can function to positively regulate transcription.

Inactivation of the retinoblastoma tumor suppressor protein, Rb, is necessary for the normal progression of the mammalian cell cycle.[] Studies over the past fifteen years have shown that Rb protein is inactivated by kinases associated with cyclins, especially cyclins D and E, which facilitate the entry of cells from the G1 to S phase.[]–[] Though the cyclin/cdk mediated inactivation of Rb has been well studied, the role of other kinases in regulating Rb function is relatively less understood.[] It has been shown that components of the MAP kinase cascade, including ERK kinases as well as the Raf-1 kinase can phosphorylate Rb efficiently in response to proliferative signals.[],[] A physiological role for Raf-1 in inactivating Rb during cell cycle progression has been established.[] These kinases seem to work in conjunction with the cyclin-cdks, facilitating phosphorylation by the latter; at the same time, over-expression of Raf-1 could inactivate Rb as efficiently as cyclin-cdks. [],[] Similarly, it has been shown that Rb is inactivated upon apoptotic signaling as well.[]–[] Such inactivation events appear to be mediated by the p38 kinase in a human T-cell leukemia system as well as a neuronal system.[],[] The inactivation of Rb upon apoptotic signaling seems to be totally independent of cyclins and cdks and occurring on different sites on the Rb protein.[] In addition to the p38 kinase, the stress-induced kinase JNK1 has been shown to affect Rb and E2F functions in certain apoptotic situations.[],[] Recently, the apoptosis signal regulating kinase, ASK1, was found to interact with Rb and overcome its anti-apoptotic activities.[] These studies suggest that while cyclin dependent kinases are the predominant regulators of Rb, especially during cell cycle progression, other kinases are capable of functionally inactivating Rb in response to multiple stimuli. Since inactivation of the Rb protein is widespread in a wide array of human tumors,[],[],[] understanding the mechanisms that inactivate Rb in response to normal physiological stimuli would be valuable in developing novel therapeutic strategies to combat cancer.

E2F activity is largely controlled by cell cycle dependent phosphorylation of the retinoblastoma family of proteins (e.g., pRB). Regulation of E2F transcription factors by RB-family proteins is crucial to the regulation of cell cycle entry. In addition to masking E2F activation of transcription, pRB family proteins have been implicated in nucleating transcriptional repressor complexes containing E2F transcription factors on cell cycle regulated promoters. More recently E2F transcription factors have been shown to regulate the activity of cellular processes in differentiation and apoptosis in a manner that is independent of cell cycle control. These recent findings have revealed that E2F transcription factors participate in noncell cycle regulatory mechanisms.

The retinoblastoma protein Rb, when targeted to E2F-responsive promoters through a direct interaction with E2F proteins, actively represses transcription. This property is shared by the two Rb-related proteins, p107 and p130. Active transcriptional repression by Rb is important for the proper control of cell growth. Many recent results have indicated that Rb represses transcription through proteins acting on chromatin structure. The purpose of this chapter is to review these results, and to discuss the possible mechanisms by which accurate regulation of E2F-responsive genes is achieved.

Research on the retinoblastoma protein has grown from studying its role as a tumour suppressor in cancer to identifying it as a key regulator of the cell cycle G1/S check point and today to exploring its function in numerous cellular processes. The recent development of conditional knockout mice has shed new light on the roles of Rb in embryonic development and has aided in the identification of the cell-of-origin in Retinoblastoma cancer. In this review, we will discuss the role of Rb as a tumour suppressor as well as its role in cell division, differentiation, apoptosis and cancer.

The pivotal role of the Retinoblastoma gene product pllO (pRb) in cellular differentiation has been postulated since the identification of pRb as a target of oncogenic events. The demonstration of the essential role of pRb during terminal differentiation of many tissues appeared evident along with the identification of the critical properties of pRb in regu-lating cell cycle progression and apoptosis. Permanent cell cycle arrest and resistance to both tumor formation and apoptosis are three cardinal features of terminal differentiation. Upon functional or genetic inactivation of pRb, cells from skeletal muscle, neuronal and hematopoi-etic lineages exhibit higher extent of apoptosis, fail to permanently exit the cell cycle and showincomplete differentiation.