The accidental cancer geneticist: Hilário de Gouvêa and hereditary retinoblastoma

Abstract

In 1872 a Brazilian ophthalmologist performed an enucleation in a young boy with retinoblastoma. This boy survived and married a woman without any family history of cancer. The couple had two daughters with bilateral retinoblastoma also seen by the same ophthalmologist, Hilário de Gouvêa. This case became the first documented report of a family with retinoblastoma in more than one generation. Here we examine the life of de Gouvêa and his contribution which raised the possibility that cancer had a genetic basis. We discuss how de Gouvêa's mind had been prepared to realize the importance of this observation. We attempt to define the conditions that allowed not only his discovery, but also the report of the findings and a dogged pursuit for credit over many years in a country which had virtually no research tradition and was still grappling with its recent colonial history.

Evidence for the Possible Biological Significance of the igf-1 Gene Alternative Splicing in Prostate Cancer

“…This downstream cascade includes the activation of the small G protein Ras followed by the activation of protein serine kinase Raf, which in turn activates the MEK/MAPK pathway (Figure 3). The final products of this pathway modulate cell proliferation and differentiation via transduction of mitogenic signals through activation of transcription factors (Davis, 1995; Papatsoris et al, 2007; Ozkan, 2011), such as ELK-1, CREB, Gata-1, Fos (Garcia et al, 2006; Steelman et al, 2011), and AP-1 (Kajanne et al, 2009). At the cellular level, IGF-IR increases DNA synthesis and stimulates, through activation of MAPK pathway, the expression of cyclin D1, which accelerates the progression of the cell cycle from G1 to S phase (Furlanetto et al, 1994; Yu and Rohan, 2000; Papatsoris et al, 2007) (Figure 3).…”

“…MAP kinases are key mediators of eukaryotic transcriptional responses to extracellular signals and control gene expression via the phosphorylation and regulation of co-regulatory proteins and transcription factors (Papatsoris and Papavassiliou, 2001; Papatsoris et al, 2007; Whitmarsh, 2007; Kaminska et al, 2009; Kim and Choi, 2010). Specifically, one of the pathways that leads from growth factor receptor tyrosine kinases to MAP kinases involves Shc, Grb2, Sos, Ras, Raf, and MKKs; Shc binds to phosphorylated tyrosines on activated IGF-IR tyrosine kinases and the subsequent phosphorylation of Shc generates a binding site for the Grb2, while this binding is thought to generate a Shc/Grb2/Sos complex.…”

“…The activation of Ras/Raf signals to MKKs (specifically MEK1/2) and these kinases phosphorylate and activate ERKs (ERK1/2), which then can activate by phosphorylation both, other protein kinases and several transcription factors (Figure 3). Ras mediates the activation of various effector pathways that modulate cell proliferation, apoptosis, and other cellular processes (Papatsoris et al, 2007), while further, the ability of the Ras/MAPK pathway to regulate cell proliferation, differentiation, and survival in prostate appears to be dependent upon the amplitude and duration of the MAPK activation (Maroni et al, 2004; Papatsoris et al, 2007). MAP kinase cascades include three major groups of signaling cascades in humans, namely ERK1/2, JNK, and p38 cascade.…”

“…The ERK cascade is a highly conserved signaling pathway throughout eukaryotic cells, integrating signals that modulate many cellular processes such as cell cycle, proliferation, survival, differentiation, and cell migration (Bodart, 2010). Upon their activation (phosphorylation), ERK1/2 phosphorylate transcription factors present in the cytoplasm or nucleus, thus leading to expression of target genes and resulting in biological responses (Papatsoris and Papavassiliou, 2001; Papatsoris et al, 2007; Kaminska et al, 2009). In this context, the ERK signaling pathway also plays a role in several other steps of tumor development, including the cancer cell migration and tumor invasion, by inducing the expression of matrix metalloproteinases and thereby promoting the degradation of extracellular matrix proteins (Kim and Choi, 2010).…”

“…In this context, the ERK signaling pathway also plays a role in several other steps of tumor development, including the cancer cell migration and tumor invasion, by inducing the expression of matrix metalloproteinases and thereby promoting the degradation of extracellular matrix proteins (Kim and Choi, 2010). The effects of phosphorylated ERK1/2 on PCa cells can be particularly the enhancement of cellular proliferation as well a reduction of apoptosis and, thus, the relative activation of ERK1 and ERK2 could have variable cellular effects in prostate carcinogenesis (Papatsoris et al, 2007). However, growth, survival, or androgen responsiveness of PCa cells are not exclusively mediated by the Ras/MAPK cascade and other molecular mechanisms also converge to this pathway (Papatsoris et al, 2007).…”