Cyclin I Protects Podocytes from Apoptosis

Abstract

The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (؊/؊) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I ؊/؊ mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21Cip1/Waf1 protects podocytes from certain apoptotic stimuli. In cultured cyclin I ؊/؊ podocytes, the level of p21Cip1/Waf1 was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild-type cells. Enforced expression of p21Cip1/Waf1 reversed the susceptibility of cyclin I ؊/؊ podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21 Cip1/Waf1 .Cyclins were originally discovered for their role in governing cell cycle progression and proliferation (1). More recently it has been appreciated that cyclins may influence a wide range of additional cellular functions, including apoptosis, hypertrophy, and differentiation. The increasingly diverse members of the cyclin protein family are all characterized by the presence of a conserved domain through which they bind to cyclin-dependent kinases, the cyclin box (2). Cyclin I, the focus of this manuscript, is most abundant in post-mitotic tissues. In contrast to the classical cyclins, its level does not fluctuate during the cell cycle (3, 4). Cyclin I shows highest sequence homology to cyclins G1 and G2, and these three proteins are considered to form a separate subgroup (5). However, the biological function of cyclin I is not known.Our data show that within the kidney cyclin I is specifically expressed by glomerular podocytes. These are terminally differentiated, post-mitotic, highly specialized epithelial cells, which serve as the major barrier to prevent the excretion of serum proteins into the urine. The inability to replace podocytes lost by apoptosis is thought to underlie the subsequent development of glomerulosclerosis and progressive renal impairment, regardless of the initiating injury (6 -14). Given their limited regenerative capacity, prevention of podocyte apoptosis is of critical importance for the maintenance of normal renal function.The restricted expression of cyclin I to the renal podocyte suggested that it might play a specialized biological role in these cells. We describe here the characterization of cyclin I expression in the normal kidney and the first analysis of its function using cyclin I knock-out mice. We report that cyclin I regulates podocyte apoptosis, both ...

Cyclin I-Cdk5 governs survival in post-mitotic cells

“…8 In contrast to other cyclins its mRNA levels do not fluctuate during the cell cycle. [5][6][7] Moreover, we showed that Cyclin I null mice are normal, consistent with the notion that Cyclin I is not required for cell differentiation. The Cyclin I null mouse, and subsequent cell culture studies using cells isolated from these mice such as fibroblasts and podocytes, showed that in contrast to other cyclins, Cyclin I has no role in regulating cell proliferation.…”

“…This paradigm has since been altered by the discovery of atypical cyclin proteins and dependent kinases including cyclin C-Cdk8, 1 cyclin H-Cdk7, 2 cyclin K-Cdk9, 3 cyclin T-Cdk9, 4 or Cyclin I. [5][6][7] Cyclin I, first cloned from human forebrain cortex, shows highest sequence homology to cyclins G 1 and G 2 . 8 In contrast to other cyclins its mRNA levels do not fluctuate during the cell cycle.…”

“…The Cyclin I null mouse, and subsequent cell culture studies using cells isolated from these mice such as fibroblasts and podocytes, showed that in contrast to other cyclins, Cyclin I has no role in regulating cell proliferation. 5 On further reflection, Cyclin I is predominantly constitutively expressed in terminally differentiated and quiescent cells such as neurons, 8 podocytes 5 or cardiomyocytes, 9 cells which typically do not proliferate when they reach their mature adult form. Liu et al reported an increased Cyclin I protein expression in cardiomyocytes upon growth arrest and differentation.…”

RNA-binding protein nucleolin in disease

“…These mRNAs included those that encode the prosurvival proteins Akt1 and cyclin I. 13,56,57 Akt is one of the most active kinases in cancer cells, while the anti-apoptotic protein cyclin I is highly expressed in breast cancer and its increased level in serum is associated with pancreatic cancer. 56,58,59 Nucleolin and microRNA processing.…”

FOXA1 Is Essential for Aryl Hydrocarbon Receptor–Dependent Regulation of Cyclin G2

“…The G-type cyclins (cyclin G1, G2, and I) on the other hand are associated with cell-cycle arrest (15). Cyclin G1 is involved in G 2 -M phase arrest, whereas cyclin I is thought to play a role in apoptosis (16). Cyclin G2 (CCNG2) has been shown to inhibit cell-cycle progression by preventing G 1 to S-phase transition (14,15,17).…”