p53, the Cellular Gatekeeper for Growth and Division

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

Gene regulation by steroid hormones.

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

Inhibitors of mammalian G1 cyclin-dependent kinases.

Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

/pdf/live-or-let-die-the-cell-s-response-to-p53-3v8en5zmb2.pdf

Live or let die: the cell's response to p53

Complementary DNAs (cDNAs) encoding androgen receptors were obtained from human testis and rat ventral prostate cDNA libraries. The amino acid sequence deduced from the nucleotide sequences of the cDNAs indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors. The human cDNA was transcribed and the RNA product was translated in cell-free systems to yield a 76-kilodalton protein. The protein was immunoprecipitable by human autoimmune antibodies to the androgen receptor. The protein bound androgens specifically and with high affinity.

https://science.sciencemag.org/content/sci/240/4850/324.full.pdf

Molecular Cloning of Human and Rat Complementary DNA Encoding Androgen Receptors

Deregulated expression of the c-myc proto-oncogene can lead to apoptosis under certain physiological conditions. By introducing a conditionally active Myc allele into primary embryo fibroblasts null for p53, and into fibroblasts without endogenous p53 expression but ectopically expressing a temperature-sensitive p53 allele, we show that expression of wild-type p53 is required for susceptibility to Myc-mediated apoptosis. Although ectopic expression of wild-type p53 blocked cells in the G1 phase of the cell cycle, G1 arrest by isoleucine starvation, in a manner independent of p53, did not confer susceptibility to apoptosis. Thus, growth arrest per se is not sufficient to induce Myc-mediated apoptosis; instead, a property intrinsic to p53 is specifically required. Moreover, apoptosis did not require induction of p53 target proteins, including the cyclin-dependent kinase inhibitor p21waf1/cip1. Therefore, the role of p53 in apoptosis may be distinct from its role in cell cycle arrest.

/pdf/myc-mediated-apoptosis-requires-wild-type-p53-in-a-manner-179mqmu395.pdf

Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1.

Structural analysis of cDNAs for human and rat androgen receptors (ARs) indicates that the amino-terminal regions of ARs are rich in oligo- and poly(amino acid) motifs as in some homeotic genes. The human AR has a long stretch of repeated glycines, whereas rat AR has a long stretch of glutamines. There is a considerable sequence similarity among ARs and the receptors for glucocorticoids, progestins, and mineralocorticoids within the steroid-binding domains. The cysteine-rich DNA-binding domains are well conserved. Translation of mRNA transcribed from AR cDNAs yielded 94- and 76-kDa proteins and smaller forms that bind to DNA and have high affinity toward androgens. These rat or human ARs were recognized by human autoantibodies to natural ARs. Molecular hybridization studies, using AR cDNAs as probes, indicated that the ventral prostate and other male accessory organs are rich in AR mRNA and that the production of AR mRNA in the target organs may be autoregulated by androgens.

https://www.pnas.org/content/pnas/85/19/7211.full.pdf

Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors.

Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate

The cDNA for a member of the nuclear receptor family was cloned and named ubiquitous receptor (UR), since UR protein and mRNA are detected in many cell types. Rat UR/human retinoid X receptor alpha (hRXR alpha) heterodimers bound preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence AGGTCA and 4-nt spacing (DR-4). Coexpression of UR in COS-1 cells inhibited the stimulation of chloramphenicol acetyltransferase (CAT) reporter gene expression by hRXR alpha and human retinoic acid receptor alpha in the presence of all-trans-retinoic acid when DR-4 (but not DR-5) was present upstream of the promoter of a CAT reporter gene (DR-4-CAT). UR expression also inhibited the activation of a DR-4-CAT reporter gene by hRXR alpha and 9-cis-retinoic acid or by thyroid hormone receptor beta in the presence of thyroid hormone. However, in the absence of 9-cis-retinoic acid, UR in combination with hRXR alpha stimulation DR-4-CAT expression. Coexpression of thyroid hormone receptor markedly reduced this stimulation in the absence of thyroid hormone. UR may play an important role in normal growth and differentiation by modulating gene activation in retinoic acid and thyroid hormone signaling pathways.

/pdf/ubiquitous-receptor-a-receptor-that-modulates-gene-3kfswss5ec.pdf

John M. Kokontis

Papers

Molecular Cloning of Human and Rat Complementary DNA Encoding Androgen Receptors

Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1.

Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors.

Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate

Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors.