Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

/pdf/inhibitors-of-mammalian-g1-cyclin-dependent-kinases-38eef2u6ay.pdf

Inhibitors of mammalian G1 cyclin-dependent kinases.

Much has been written about the functions of the E2F transcription factor and the product of the retinoblastoma tumor suppressor gene (pRB). These proteins have been described in terms that vary from ‘‘master regulators of cell cycle and differentiation’’ to ‘‘peripheral factors that lie outside the core cell cycle machinery.’’ Most often, pRB and E2F are described in short and simple terms as opposing molecules that control the G1to Sphase transition. There is an element of truth in each of these descriptions. E2Fand pRB-family proteins clearly play important roles in cell proliferation and differentiation. The extent to which they are master regulators or peripheral factors is a question of semantics, and these terms tell us more about the writer than the proteins. Perhaps the most important development in the E2F literature is the appreciation that E2F and pRB are not unique molecules with functions that can be defined in black and white terms. Instead, E2F and pRB represent families of related proteins that have diverse and occasionally contradictory activities. We now know a great deal about E2F complexes and pRB-family proteins and the emerging picture defies a one-line explanation. The fascinating variety of activities ascribed to various E2F complexes challenges us to place these into context and to find the right perspective. This review is presented into two sections. The first section summarizes the tremendous progress into the composition and properties of E2F and the many interactions that coordinately regulate E2F-dependent transcription. The rapid growth in the size of the E2F literature hides the fact that several fundamental questions have not been fully answered. Because of this, the second section of this review details five unresolved issues that have been highlighted by recent publications. It is impossible to cover all of the relevant E2F literature in a single review and readers are referred to reviews by Farnham (1995); Sardet et al. (1997); Helin (1998); and Yamasaki (1998) for a comprehensive survey.

http://genesdev.cshlp.org/content/12/15/2245.full.pdf

The regulation of E2F by pRB-family proteins

Tumor spectrum analysis in p53-mutant mice.

https://staff.washington.edu/andchien/PDFs/cell-bccpatched.pdf

Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome

The retinoblastoma gene, a prototypic tumour-suppressor gene, encodes a nuclear phosphoprotein (Rb). To understand better the role of Rb in development and in tumorigenesis, mice with an insertional mutation in exon 20 of the Rb-1 locus were generated. Homozygous mutants die before the 16th embryonic day with multiple defects. The haematopoietic system is abnormal; there is a significant increase in the number of immature nucleated erythrocytes. In the nervous system, ectopic mitoses and massive cell death are found, particularly in the hindbrain. All spinal ganglion cells die, but the neural retina is unaffected. Transfer of the human retinoblastoma (RB) mini-transgene into the mutant mice corrects the developmental defects. Thus, Rb is essential for normal mouse development.

Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.

Genetic alterations or predisposition of human cancers have been studied extensively in the last few decades (1–3) These genetic changes, which may be responsible for the genesis of cancers, can either be inherited or occur as a result of somatic mutation In many cases of heritable human cancers, such as retinoblastoma (RB), Wilms’ tumor (nephroblastoma) and familial polyposis (4–6), the transmission of these genetic defects in affected families is suggested to render them at higher risk and/or higher susceptibility to certain types of cancer (7,8) One of the most well studied heritable cancers is retinoblastoma Retinoblastoma occurs in young children at an incidence of about 1 in 20,000 live births and it is the most common intraocular tumor of the pediatric age group (9) Two forms of retinoblastoma are distinguished based on their genetic origins (10) Typically, bilateral and/or multifocal retinoblastoma occurs in hereditary cases which comprise 40% of all retinoblastomas The hereditary form of retinoblastoma is transmitted as an autosomaldominant trait with 90% penetrance (11,12) In addition to the occurrence of childhood retinoblastomas, those people carrying the trait often develop secondary primary tumors, such as osteosarcoma or fibrosarcoma, at higher incidence than the normal population (13,14)

Chen-Ching Lai

Papers

Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.

Human retinoblastoma susceptibility gene.